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1
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Orzetti S, Baldo P. Toxicity Derived from Interaction between Natural Compounds and Cancer Therapeutic Drugs Metabolized by CYP3A4: Lessons Learned from Two Clinical Case Reports. Int J Mol Sci 2023; 24:15976. [PMID: 37958959 PMCID: PMC10648905 DOI: 10.3390/ijms242115976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/01/2023] [Accepted: 11/02/2023] [Indexed: 11/15/2023] Open
Abstract
The use of natural compounds and, in general, the use of Complementary and Alternative Medicine (CAM), is growing steadily worldwide, both due to commercial pressure and the increasing use of self-medication and the desire to manage one's own personal health and well-being. Patients facing a cancer diagnosis are also strongly pressured to use these compounds, which are often added to standard therapeutic regimens, that should instead be based solely on diagnostic and therapeutic care pathways (DTCP) or evidence-based medicine (EBM). This study presents two clinical cases of cancer patients who presented to the pharmaceutical consultation service (PCD-Pharmacy Clinical Desk) established at the CRO Institute in Aviano, Italy. Both patients were using natural products along with prescribed chemotherapy. In the first case, a 55-year-old woman diagnosed with bilateral breast cancer with bone metastases, who was using natural compounds based on diosmin, escin (or aescin) and resveratrol in combination with ribociclib anticancer therapy, a severe ADR (neutropenia) was identified as a consequence of the drug-natural product interaction. In the second case, following a detailed medication review by the PCD, we avoided taking a therapeutic treatment (with natural compounds) that in itself could potentially render chemotherapy ineffective in a 57-year-old woman with multiple infiltrating ductal carcinoma of the left breast; the patient was planning to take a natural product containing St. John's Wort tincture and lemon balm tincture, in combination with paclitaxel and trastuzumab. In addition, we describe the corrective actions taken, thus outlining the main objectives of the activity of the PCD's pharmacy counseling service: first, to identify, report, and manage adverse drug reactions (ADRs), and second, to identify therapeutic combinations that present potential risks of toxicity or ineffectiveness of the drug therapy itself.
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Affiliation(s)
- Sabrina Orzetti
- PCD Pharmacy Clinical Desk, Hospital Pharmacy Unit of the “Centro di Riferimento Oncologico (CRO) di Aviano IRCCS”, Via F. Gallini, 33081 Aviano, Italy;
| | - Paolo Baldo
- Hospital Pharmacy Unit of the “Centro di Riferimento Oncologico (CRO) di Aviano IRCCS”, Via F. Gallini, 33081 Aviano, Italy
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2
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Rungratanawanich W, Ballway JW, Wang X, Won KJ, Hardwick JP, Song BJ. Post-translational modifications of histone and non-histone proteins in epigenetic regulation and translational applications in alcohol-associated liver disease: Challenges and research opportunities. Pharmacol Ther 2023; 251:108547. [PMID: 37838219 DOI: 10.1016/j.pharmthera.2023.108547] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 09/30/2023] [Accepted: 10/05/2023] [Indexed: 10/16/2023]
Abstract
Epigenetic regulation is a process that takes place through adaptive cellular pathways influenced by environmental factors and metabolic changes to modulate gene activity with heritable phenotypic variations without altering the DNA sequences of many target genes. Epigenetic regulation can be facilitated by diverse mechanisms: many different types of post-translational modifications (PTMs) of histone and non-histone nuclear proteins, DNA methylation, altered levels of noncoding RNAs, incorporation of histone variants, nucleosomal positioning, chromatin remodeling, etc. These factors modulate chromatin structure and stability with or without the involvement of metabolic products, depending on the cellular context of target cells or environmental stimuli, such as intake of alcohol (ethanol) or Western-style high-fat diets. Alterations of epigenetics have been actively studied, since they are frequently associated with multiple disease states. Consequently, explorations of epigenetic regulation have recently shed light on the pathogenesis and progression of alcohol-associated disorders. In this review, we highlight the roles of various types of PTMs, including less-characterized modifications of nuclear histone and non-histone proteins, in the epigenetic regulation of alcohol-associated liver disease (ALD) and other disorders. We also describe challenges in characterizing specific PTMs and suggest future opportunities for basic and translational research to prevent or treat ALD and many other disease states.
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Affiliation(s)
- Wiramon Rungratanawanich
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA
| | - Jacob W Ballway
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Kyoung-Jae Won
- Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA, 90069, USA
| | - James P Hardwick
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA.
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3
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Kluska M, Jabłońska J, Prukała W. Analytics, Properties and Applications of Biologically Active Stilbene Derivatives. Molecules 2023; 28:molecules28114482. [PMID: 37298957 DOI: 10.3390/molecules28114482] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/18/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
Stilbene and its derivatives belong to the group of biologically active compounds. Some derivatives occur naturally in various plant species, while others are obtained by synthesis. Resveratrol is one of the best-known stilbene derivatives. Many stilbene derivatives exhibit antimicrobial, antifungal or anticancer properties. A thorough understanding of the properties of this group of biologically active compounds, and the development of their analytics from various matrices, will allow for a wider range of applications. This information is particularly important in the era of increasing incidence of various diseases hitherto unknown, including COVID-19, which is still present in our population. The purpose of this study was to summarize information on the qualitative and quantitative analysis of stilbene derivatives, their biological activity, potential applications as preservatives, antiseptics and disinfectants, and stability analysis in various matrices. Optimal conditions for the analysis of the stilbene derivatives in question were developed using the isotachophoresis technique.
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Affiliation(s)
- Mariusz Kluska
- Faculty of Sciences, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland
| | - Joanna Jabłońska
- Faculty of Sciences, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland
| | - Wiesław Prukała
- Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland
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4
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Liao J, Lu Q, Li Z, Li J, Zhao Q, Li J. Acetaminophen-induced liver injury: Molecular mechanism and treatments from natural products. Front Pharmacol 2023; 14:1122632. [PMID: 37050900 PMCID: PMC10083499 DOI: 10.3389/fphar.2023.1122632] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 03/13/2023] [Indexed: 03/29/2023] Open
Abstract
Acetaminophen (APAP) is a widely used analgesic and antipyretic over-the-counter medicine worldwide. Hepatotoxicity caused by APAP overdose is one of the leading causes of acute liver failure (ALF) in the US and in some parts of Europe, limiting its clinical application. Excessive APAP metabolism depletes glutathione and increases N-acetyl-p-benzoquinoneimide (NAPQI) levels, leading to oxidative stress, DNA damage, and cell necrosis in the liver, which in turn leads to liver damage. Studies have shown that natural products such as polyphenols, terpenes, anthraquinones, and sulforaphane can activate the hepatocyte antioxidant defense system with Nrf2 as the core player, reduce oxidative stress damage, and protect the liver. As the key enzyme metabolizing APAP into NAPQI, cytochrome P450 enzymes are also considered to be intriguing target for the treatment of APAP-induced liver injury. Here, we systematically review the hepatoprotective activity and molecular mechanisms of the natural products that are found to counteract the hepatotoxicity caused by APAP, providing reference information for future preclinical and clinical trials of such natural products.
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Affiliation(s)
- Jiaqing Liao
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Pharmacy, Chengdu University, Chengdu, China
| | - Qiuxia Lu
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Food and Biological Engineering, Chengdu University, Chengdu, China
| | - Zhiqi Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Food and Biological Engineering, Chengdu University, Chengdu, China
| | - Jintao Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Pharmacy, Chengdu University, Chengdu, China
| | - Qi Zhao
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Food and Biological Engineering, Chengdu University, Chengdu, China
- *Correspondence: Qi Zhao, ; Jian Li,
| | - Jian Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
- *Correspondence: Qi Zhao, ; Jian Li,
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5
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Han DG, Seo SW, Choi E, Kim MS, Yoo JW, Jung Y, Yoon IS. Impact of route-dependent phase-II gut metabolism and enterohepatic circulation on the bioavailability and systemic disposition of resveratrol in rats and humans: A comprehensive whole body physiologically-based pharmacokinetic modeling. Biomed Pharmacother 2022; 151:113141. [PMID: 35609369 DOI: 10.1016/j.biopha.2022.113141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/09/2022] [Accepted: 05/15/2022] [Indexed: 11/02/2022] Open
Abstract
Resveratrol, a natural polyphenolic phytoalexin, is a dietary supplement that improves the outcomes of metabolic, cardiovascular, and other age-related diseases due to its diverse pharmacological activities. Although there have been several preclinical and clinical investigations of resveratrol, the contributions of gut phase-II metabolism and enterohepatic circulation to the oral bioavailability and pharmacokinetics of resveratrol remain unclear. Furthermore, a physiologically-based pharmacokinetic (PBPK) model that accurately describes and predicts the systemic exposure profiles of resveratrol in clinical settings has not been developed. Experimental data were acquired from several perspectives, including in vitro protein binding and blood distribution, in vitro tissue S9 metabolism, in situ intestinal perfusion, and in vivo pharmacokinetics and excretion studies. Using these datasets, an in-house whole-body PBPK model incorporating route-dependent phase-II (glucuronidation and sulfation) gut metabolism and enterohepatic circulation processes was constructed and optimized for chemical-specific parameters. The developed PBPK model aligned with the observed systemic exposure profiles of resveratrol in single and multiple dosing regimens with an acceptable accuracy of 0.538-0.999-fold errors. Furthermore, the model simulations elucidated the substantial contribution of gut first-pass metabolism to the oral bioavailability of resveratrol and suggested differential effects of enterohepatic circulation on the systemic exposure of resveratrol between rats and humans. After partial modification and verification, our proposed PBPK model would be valuable to optimize dosage regimens and predict food-drug interactions with resveratrol-based natural products in various clinical scenarios.
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Affiliation(s)
- Dong-Gyun Han
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea
| | - Seong-Wook Seo
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea
| | - Eugene Choi
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea
| | - Min-Soo Kim
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea
| | - Jin-Wook Yoo
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea
| | - Yunjin Jung
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea
| | - In-Soo Yoon
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea.
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6
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Zhang Y, Yan T, Wang T, Liu X, Hamada K, Sun D, Sun Y, Yang Y, Wang J, Takahashi S, Wang Q, Krausz KW, Jiang C, Xie C, Yang X, Gonzalez FJ. Crosstalk between CYP2E1 and PPAR α substrates and agonists modulate adipose browning and obesity. Acta Pharm Sin B 2022; 12:2224-2238. [PMID: 35646522 PMCID: PMC9136617 DOI: 10.1016/j.apsb.2022.02.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/11/2022] [Accepted: 01/28/2022] [Indexed: 11/24/2022] Open
Abstract
Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα–FGF21–beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.
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7
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Cote B, Elbarbry F, Bui F, Su JW, Seo K, Nguyen A, Lee M, Rao DA. Mechanistic Basis for the Role of Phytochemicals in Inflammation-Associated Chronic Diseases. Molecules 2022; 27:molecules27030781. [PMID: 35164043 PMCID: PMC8838908 DOI: 10.3390/molecules27030781] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/14/2022] [Accepted: 01/21/2022] [Indexed: 12/15/2022] Open
Abstract
Chronic inflammatory diseases occur in a large portion of the population and are associated with a poor diet. Key natural products found in fruits and vegetables may assist in lowering inflammation associated with chronic diseases such as obesity, diabetes, cardiovascular diseases, and cancer. This review seeks to examine the roles of several natural products, resveratrol (RES), quercetin (QUE), curcumin (CUR), piperine (PIP), epigallocatechin gallate (EGCG), and gingerol (GIN), in their ability to attenuate inflammatory markers in specific diseases states. Additionally, we will discuss findings in past and ongoing clinical trials, detail possible phytochemical–drug interactions, and provide a brief resource for researchers and healthcare professionals on natural product and supplement regulation as well as names of databases with information on efficacy, indications, and natural product–drug interactions. As diet and over-the-counter supplement use are modifiable factors and patients are interested in using complementary and alternative therapies, understanding the mechanisms by which natural products have demonstrated efficacy and the types of drugs they interact with and knowing where to find information on herbs and supplements is important for practicing healthcare providers and researchers interested in this field.
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Affiliation(s)
- Brianna Cote
- College of Pharmacy, Oregon State University, Portland, OR 97201, USA;
| | - Fawzy Elbarbry
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Fiona Bui
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Joe W. Su
- School of Pharmacy, West Coast University, Los Angeles, CA 90004, USA;
| | - Karen Seo
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Arthur Nguyen
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Max Lee
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Deepa A. Rao
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
- Correspondence:
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8
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Morales-Rubio R, Amador-Muñoz O, Rosas-Pérez I, Sánchez-Pérez Y, García-Cuéllar C, Segura-Medina P, Osornio-Vargas Á, De Vizcaya-Ruiz A. PM 2.5 induces airway hyperresponsiveness and inflammation via the AhR pathway in a sensitized Guinea pig asthma-like model. Toxicology 2021; 465:153026. [PMID: 34774659 DOI: 10.1016/j.tox.2021.153026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 10/28/2021] [Accepted: 11/02/2021] [Indexed: 01/09/2023]
Abstract
Exposure to fine particulate matter (PM2.5) induces airway inflammation and hyperreactivity that lead to asthma. The mechanisms involved are still under investigation. We investigated the effect of resveratrol (3,4',5-trihydroxystilbene) (RES) on airway hyperresponsiveness, inflammation and CYP1A1 protein expression (an aryl hydrocarbon receptor (AhR) target) induced by PM2.5 exposure in an allergic asthma experimental guinea pig model. The polyphenolic compound RES was used due to its antioxidant and anti-inflammatory properties and as an antagonist of the AhR; thus, providing mechanistic insights. Animals were sensitized with aluminum hydroxide and ovalbumin and exposed to filtered air or PM2.5. Exposure to PM2.5 was conducted using a whole-body chamber particle concentrator (5 h/day) for 15 days. Animals received saline solution or RES (10 mg/kg per day) orally for 21 days simultaneously to the OVA challenge or PM2.5 exposure. PM2.5 exposure (mean 433 ± 111 μg/m3 in the exposure chamber) in OVA challenged animals induced an asthma-like phenotype characterized by increased baseline lung resistance (Rrs) and central airway resistance (Rn) in response to acetylcholine (ACh) evaluated using a flexiVent system®. A parallel increase of pro-inflammatory cytokines (IL-6, IL-17, TNF-α and IFN-γ), inflammatory cells (eosinophils and neutrophils) in bronchoalveolar lavage fluid (BALF) and lung CYP1A1 increase also occurred. RES significantly inhibited airway hyperresponsiveness, inflammation, and CYP1A1 protein expression in the OVA-challenged PM2.5 exposed animals. In summary, with the use of RES we demonstrate that PM-induced airway hyperreactivity is modulated by the inflammatory response via the AhR pathway in an allergic asthma guinea pig model.
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Fujino C, Sanoh S, Katsura T. Variation in Expression of Cytochrome P450 3A Isoforms and Toxicological Effects: Endo- and Exogenous Substances as Regulatory Factors and Substrates. Biol Pharm Bull 2021; 44:1617-1634. [PMID: 34719640 DOI: 10.1248/bpb.b21-00332] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter-individual differences, which are caused by many endogenous and exogenous factors. Inter-individual differences can cause negative outcomes, such as adverse drug events and disease development. Therefore, it is important to understand the variations in CYP3A expression caused by endo- and exogenous factors, as well as the variation in the metabolism and kinetics of endo- and exogenous substrates. In this review, we summarize the factors regulating CYP3A expression, such as bile acids, hormones, microRNA, inflammatory cytokines, drugs, environmental chemicals, and dietary factors. In addition, variations in CYP3A expression under pathological conditions, such as coronavirus disease 2019 and liver diseases, are described as examples of the physiological effects of endogenous factors. We also summarize endogenous and exogenous substrates metabolized by CYP3A isoforms, such as cholesterol, bile acids, hormones, arachidonic acid, vitamin D, and drugs. The relationship between the changes in the kinetics of these substrates and the toxicological effects in our bodies are discussed. The usefulness of these substrates and metabolites as endogenous biomarkers for CYP3A activity is also discussed. Notably, we focused on discrimination between CYP3A4, CYP3A5, and CYP3A7 to understand inter-individual differences in CYP3A expression and function.
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Affiliation(s)
- Chieri Fujino
- Laboratory of Clinical Pharmaceutics and Therapeutics, College of Pharmaceutical Sciences, Ritsumeikan University
| | - Seigo Sanoh
- Graduate School of Biomedical and Health Sciences, Hiroshima University.,School of Pharmaceutical Sciences, Wakayama Medical University
| | - Toshiya Katsura
- Laboratory of Clinical Pharmaceutics and Therapeutics, College of Pharmaceutical Sciences, Ritsumeikan University
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Ji SB, Park SY, Bae S, Seo HJ, Kim SE, Lee GM, Wu Z, Liu KH. Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes. Pharmaceutics 2021; 13:pharmaceutics13091419. [PMID: 34575495 PMCID: PMC8470274 DOI: 10.3390/pharmaceutics13091419] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/29/2021] [Accepted: 09/03/2021] [Indexed: 11/16/2022] Open
Abstract
The stereoselectivity of the food drug inhibition potential of resveratrol on cytochrome P450s and uridine 5'-diphosphoglucuronosyl transferases was investigated in human liver microsomes. Resveratrol enantiomers showed stereoselective inhibition of CYP2C9, CYP3A, and UGT1A1. The inhibitions of CYP1A2, CYP2B6, and CYP2C19 by resveratrol were stereo-nonselective. The estimated Ki values determined for CYP1A2 were 13.8 and 9.2 μM for trans- and cis-resveratrol, respectively. Trans-resveratrol noncompetitively inhibited CYP3A and UGT1A1 activities with Ki values of 23.8 and 27.4 μM, respectively. Trans-resveratrol inhibited CYP1A2, CYP2C19, CYP2E1, and CYP3A in a time-dependent manner with Ki shift values >2.0, while cis-resveratrol time-dependently inhibited CYP2C19 and CYP2E1. The time-dependent inhibition of trans-resveratrol against CYP3A4, CYP2E1, CYP2C19, and CYP1A2 was elucidated using glutathione as a trapping reagent. This information helped the prediction of food drug interaction potentials between resveratrol and co-administered drugs which are mainly metabolized by UGT1A1, CYP1A2, CYP2C19, CYP2E1, and CYP3A.
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Affiliation(s)
- Seung-Bae Ji
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Daegu 41566, Korea; (S.-B.J.); (S.-Y.P.); (S.B.); (H.-J.S.); (S.-E.K.); (G.-M.L.)
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Daegu 41566, Korea
| | - So-Young Park
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Daegu 41566, Korea; (S.-B.J.); (S.-Y.P.); (S.B.); (H.-J.S.); (S.-E.K.); (G.-M.L.)
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Daegu 41566, Korea
| | - Subin Bae
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Daegu 41566, Korea; (S.-B.J.); (S.-Y.P.); (S.B.); (H.-J.S.); (S.-E.K.); (G.-M.L.)
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Daegu 41566, Korea
| | - Hyung-Ju Seo
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Daegu 41566, Korea; (S.-B.J.); (S.-Y.P.); (S.B.); (H.-J.S.); (S.-E.K.); (G.-M.L.)
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Daegu 41566, Korea
| | - Sin-Eun Kim
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Daegu 41566, Korea; (S.-B.J.); (S.-Y.P.); (S.B.); (H.-J.S.); (S.-E.K.); (G.-M.L.)
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Daegu 41566, Korea
| | - Gyung-Min Lee
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Daegu 41566, Korea; (S.-B.J.); (S.-Y.P.); (S.B.); (H.-J.S.); (S.-E.K.); (G.-M.L.)
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Daegu 41566, Korea
| | - Zhexue Wu
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Daegu 41566, Korea
- Mass Spectrometry Based Convergence Research Institute, Kyungpook National University, Daegu 41566, Korea
- Correspondence: (Z.W.); (K.-H.L.); Tel.: +82-53-950-8567 (Z.W. & K.-H.L.); Fax: +82-53-950-8557 (Z.W. & K.-H.L.)
| | - Kwang-Hyeon Liu
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Daegu 41566, Korea; (S.-B.J.); (S.-Y.P.); (S.B.); (H.-J.S.); (S.-E.K.); (G.-M.L.)
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Daegu 41566, Korea
- Mass Spectrometry Based Convergence Research Institute, Kyungpook National University, Daegu 41566, Korea
- Correspondence: (Z.W.); (K.-H.L.); Tel.: +82-53-950-8567 (Z.W. & K.-H.L.); Fax: +82-53-950-8557 (Z.W. & K.-H.L.)
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11
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Zhang RX, Dong K, Wang Z, Miao R, Lu W, Wu XY. Nanoparticulate Drug Delivery Strategies to Address Intestinal Cytochrome P450 CYP3A4 Metabolism towards Personalized Medicine. Pharmaceutics 2021; 13:1261. [PMID: 34452222 PMCID: PMC8399842 DOI: 10.3390/pharmaceutics13081261] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 01/01/2023] Open
Abstract
Drug dosing in clinical practice, which determines optimal efficacy, toxicity or ineffectiveness, is critical to patients' outcomes. However, many orally administered therapeutic drugs are susceptible to biotransformation by a group of important oxidative enzymes, known as cytochrome P450s (CYPs). In particular, CYP3A4 is a low specificity isoenzyme of the CYPs family, which contributes to the metabolism of approximately 50% of all marketed drugs. Induction or inhibition of CYP3A4 activity results in the varied oral bioavailability and unwanted drug-drug, drug-food, and drug-herb interactions. This review explores the need for addressing intestinal CYP3A4 metabolism and investigates the opportunities to incorporate lipid-based oral drug delivery to enable precise dosing. A variety of lipid- and lipid-polymer hybrid-nanoparticles are highlighted to improve drug bioavailability. These drug carriers are designed to target different intestinal regions, including (1) local saturation or inhibition of CYP3A4 activity at duodenum and proximal jejunum; (2) CYP3A4 bypass via lymphatic absorption; (3) pH-responsive drug release or vitamin-B12 targeted cellular uptake in the distal intestine. Exploitation of lipidic nanosystems not only revives drugs removed from clinical practice due to serious drug-drug interactions, but also provide alternative approaches to reduce pharmacokinetic variability.
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Affiliation(s)
- Rui Xue Zhang
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi’an 710072, China; (R.X.Z.); (R.M.); (W.L.)
| | - Ken Dong
- Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada;
| | - Zhigao Wang
- College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing 210003, China;
| | - Ruimin Miao
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi’an 710072, China; (R.X.Z.); (R.M.); (W.L.)
| | - Weijia Lu
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi’an 710072, China; (R.X.Z.); (R.M.); (W.L.)
| | - Xiao Yu Wu
- Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada;
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12
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Wang P, Hu XX, Li YH, Gao NY, Chen GQ, Chen JL. Inhibitory effect of resveratrol on the pharmacokinetics of ticagrelor in vivo and in vitro. Can J Physiol Pharmacol 2021; 99:821-826. [PMID: 33400617 DOI: 10.1139/cjpp-2020-0512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human cytochrome P450 (CYP) 3A4 (CYP3A4) and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50 mg/kg resveratrol), and group C (150 mg/kg resveratrol). After 30 min administration of resveratrol, a single dose of ticagrelor (18 mg/kg) was administered orally. The in vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated ultra high-performance liquid chromatography - tandem mass spectrometer methods. For the in vivo study, the area under the concentration-time curve and mean peak plasma concentrations of ticagrelor in group B and C appeared to be significantly higher than the control group, while volume of distribution in terminal phase and apparent clearance of ticagrelor in group B and C were significantly decreased. For the in vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The half-maximal inhibitory concentration values of resveratrol were 56.75 μM, 69.07 μM, and 14.22 μM, respectively. Our results indicated that resveratrol had an inhibitory effect on the metabolism of ticagrelor in vitro and in vivo. Further research should focus on the clinical combination of resveratrol with ticagrelor, and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.
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Affiliation(s)
- Peng Wang
- Jinhua People's Hospital, Jinhua, Zhejiang, China
| | - Xiao-Xia Hu
- Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Ying-Hui Li
- Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Nan-Yong Gao
- Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guo-Quan Chen
- Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Jia-le Chen
- Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
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13
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Ueno T, Takahashi S, Nakamura T, Tanaka Y, Hori H, Mizoi K, Ogihara T. Evaluation system for cell-permeable CYP3A4 inhibitory activity using 1α,25-dihydroxy-vitamin D 3-induced intestinal cell lines. Xenobiotica 2021; 51:771-777. [PMID: 33947307 DOI: 10.1080/00498254.2021.1925375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
We developed an assay system to evaluate the cytochrome P450 (CYP) 3A4-inhibitory activity of compounds, taking account of their cellular permeability, using intestine-derived cell lines pre-treated with the CYP3A4 inducer 1α,25-dihydroxy-vitamin D3 (250 nM).Ketoconazole (KTZ), saquinavir (SQV), naringin, naringenin (NGE), bergamottin (BG), 6',7'-dihydroxybergamottin (DHBG), epigallocatechin gallate (EGCG), and resveratrol (RES) were evaluated as known CYP3A4 inhibitors. The apparent IC50 (IC50,app) values of known inhibitors were determined in Caco-2 cells with 10 µM midazolam as a CYP3A4 substrate, and compared with the IC50 values in a human liver microsome assay.SQV and BG with high lipophilicity and good membrane permeability show similar concentrations inside and outside the cells, and consequently IC50,app and IC50 are similar.KTZ, EGCG, DHBG, NGE, and RES showed a difference between IC50 and IC50,app. This is considered to result from a difference between the intracellular and extracellular concentrations of the compound, which is likely due to the involvement of efflux and/or influx transporters.This method to evaluate CYP inhibition taking account of membrane permeation should be helpful to assess the potential clinical relevance of drug-drug or drug-food interactions in the gastrointestinal tract.
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Affiliation(s)
- Toshiya Ueno
- Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan.,Suntory MONOZUKURI Expert Limited, Kyoto, Japan
| | - Saori Takahashi
- Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan
| | - Tomoya Nakamura
- Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan
| | | | - Hisako Hori
- Suntory MONOZUKURI Expert Limited, Kyoto, Japan
| | - Kenta Mizoi
- Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan
| | - Takuo Ogihara
- Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan
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14
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Gougis P, Hilmi M, Geraud A, Mir O, Funck-Brentano C. Potential Cytochrome P450-mediated pharmacokinetic interactions between herbs, food, and dietary supplements and cancer treatments. Crit Rev Oncol Hematol 2021; 166:103342. [PMID: 33930533 DOI: 10.1016/j.critrevonc.2021.103342] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 04/06/2021] [Accepted: 04/25/2021] [Indexed: 10/21/2022] Open
Abstract
Herbs, food and dietary supplements (HFDS), can interact significantly with anticancer drug treatments via cytochrome p450 isoforms (CYP) CYP3A4, CYP2D6, CYP1A2, and CYP2C8. The objective of this review was to assess the influence of HFDS compounds on these cytochromes. Interactions with CYP activities were searched for 189 herbs and food products, 72 dietary supplements in Web of Knowledge® databases. Analyses were made from 140 of 3,125 clinical trials and 236 of 3,374 in vitro, animal model studies or case reports. 18 trials were found to report direct interactions between 9 HFDS with 8 anticancer drugs. 21 HFDS were found to interact with CYP3A4, a major metabolic pathway for many anticancer drugs. All 261 HFDS were classified for their interaction with the main cytochromes P450 involved in the metabolism of anticancer drugs. We provided an easy-to-use colour-coded table to easily match potential interactions between 261 HFDS and 117 anticancer drugs.
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Affiliation(s)
- Paul Gougis
- Sorbonne Université, INSERM CIC Paris-Est, AP-HP, ICAN, Pitié-Salpêtrière Hospital, Department of Pharmacology, F-75013, Paris, France; CLIP² Galilée, Department of Medical Oncology Pitié-Salpêtrière Hospital, F-75013, Paris, France.
| | - Marc Hilmi
- Sorbonne Université, INSERM CIC Paris-Est, AP-HP, ICAN, Pitié-Salpêtrière Hospital, Department of Pharmacology, F-75013, Paris, France
| | - Arthur Geraud
- Sorbonne Université, INSERM CIC Paris-Est, AP-HP, ICAN, Pitié-Salpêtrière Hospital, Department of Pharmacology, F-75013, Paris, France; Early Drug Development Department (DITEP), Gustave Roussy, Villejuif, France
| | - Olivier Mir
- Department of Ambulatory Care, Gustave Roussy Cancer Campus, Villejuif, France
| | - Christian Funck-Brentano
- Sorbonne Université, INSERM CIC Paris-Est, AP-HP, ICAN, Pitié-Salpêtrière Hospital, Department of Pharmacology, F-75013, Paris, France
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15
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Food-Drug Interactions with Fruit Juices. Foods 2020; 10:foods10010033. [PMID: 33374399 PMCID: PMC7823305 DOI: 10.3390/foods10010033] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/13/2020] [Accepted: 12/21/2020] [Indexed: 12/26/2022] Open
Abstract
Fruit juices contain a large number of phytochemicals that, in combination with certain drugs, can cause food–drug interactions that can be clinically significant and lead to adverse events. The mechanisms behind such interactions are in most cases related to phytochemical interference with the activity of cytochrome P450 metabolizing enzymes (CYPs) or drug transporters. Moreover, alterations in their activity can have a clinical relevance if systemic exposure to the drug is decreased or increased, meaning that the pharmacological drug effects are suboptimal, or the drug will cause toxicity. In general, the common pharmacokinetic parameters found to be altered in food–drug interactions regarding fruit juices are the area under the concentration–time curve, bioavailability, and maximum plasma concentration. In most cases, the results from the drug interaction studies with fruit juices provide only limited information due to the small number of subjects, which are also healthy volunteers. Moreover, drug interactions with fruit juices are challenging to predict due to the unknown amounts of the specific phytochemicals responsible for the interaction, as well as due to the inter-individual variability of drug metabolism, among others. Therefore, this work aims to raise awareness about possible pharmacological interactions with fruit juices.
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16
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Prikhodko V, Chernyuk D, Sysoev Y, Zernov N, Okovityi S, Popugaeva E. Potential Drug Candidates to Treat TRPC6 Channel Deficiencies in the Pathophysiology of Alzheimer's Disease and Brain Ischemia. Cells 2020; 9:cells9112351. [PMID: 33114455 PMCID: PMC7692306 DOI: 10.3390/cells9112351] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/28/2020] [Accepted: 10/20/2020] [Indexed: 12/16/2022] Open
Abstract
Alzheimer’s disease and cerebral ischemia are among the many causative neurodegenerative diseases that lead to disabilities in the middle-aged and elderly population. There are no effective disease-preventing therapies for these pathologies. Recent in vitro and in vivo studies have revealed the TRPC6 channel to be a promising molecular target for the development of neuroprotective agents. TRPC6 channel is a non-selective cation plasma membrane channel that is permeable to Ca2+. Its Ca2+-dependent pharmacological effect is associated with the stabilization and protection of excitatory synapses. Downregulation as well as upregulation of TRPC6 channel functions have been observed in Alzheimer’s disease and brain ischemia models. Thus, in order to protect neurons from Alzheimer’s disease and cerebral ischemia, proper TRPC6 channels modulators have to be used. TRPC6 channels modulators are an emerging research field. New chemical structures modulating the activity of TRPC6 channels are being currently discovered. The recent publication of the cryo-EM structure of TRPC6 channels should speed up the discovery process even more. This review summarizes the currently available information about potential drug candidates that may be used as basic structures to develop selective, highly potent TRPC6 channel modulators to treat neurodegenerative disorders, such as Alzheimer’s disease and cerebral ischemia.
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Affiliation(s)
- Veronika Prikhodko
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (V.P.); (D.C.); (Y.S.); (N.Z.)
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical Pharmaceutical University, 197022 St. Petersburg, Russia;
- N.P. Bechtereva Institute of the Human Brain of the Russian Academy of Sciences, 197376 St. Petersburg, Russia
| | - Daria Chernyuk
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (V.P.); (D.C.); (Y.S.); (N.Z.)
| | - Yurii Sysoev
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (V.P.); (D.C.); (Y.S.); (N.Z.)
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical Pharmaceutical University, 197022 St. Petersburg, Russia;
- N.P. Bechtereva Institute of the Human Brain of the Russian Academy of Sciences, 197376 St. Petersburg, Russia
- Institute of Translational Biomedicine, Saint Petersburg State University, 199034 St. Petersburg, Russia
| | - Nikita Zernov
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (V.P.); (D.C.); (Y.S.); (N.Z.)
| | - Sergey Okovityi
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical Pharmaceutical University, 197022 St. Petersburg, Russia;
- N.P. Bechtereva Institute of the Human Brain of the Russian Academy of Sciences, 197376 St. Petersburg, Russia
| | - Elena Popugaeva
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (V.P.); (D.C.); (Y.S.); (N.Z.)
- Correspondence:
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17
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Zhang T, Rao J, Li W, Wang K, Qiu F. Mechanism-based inactivation of cytochrome P450 enzymes by natural products based on metabolic activation. Drug Metab Rev 2020; 52:501-530. [PMID: 33043714 DOI: 10.1080/03602532.2020.1828910] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cytochrome P450 enzymes (P450 enzymes) are the most common and important phase I metabolic enzymes and are responsible for the majority of the metabolism of clinical drugs and other xenobiotics. Drug-drug interactions (DDIs) can occur when the activities of P450 enzymes are inhibited. In particular, irreversible inhibition of P450 enzymes may lead to severe adverse interactions, compared to reversible inhibition. Many natural products have been shown to be irreversible inhibitors of P450 enzymes. The risks for intake of naturally occurring irreversible P450 enzyme inhibitors have been rising due to the rapid growth of the global consumption of natural products. Irreversible inhibition is usually called mechanism-based inactivation, which is time-, concentration- and NADPH- dependent. Generally, the formation of electrophilic intermediates is fundamental for the inactivation of P450 enzymes. This review comprehensively classifies natural P450 enzyme inactivators, including terpenoids, phenylpropanoids, flavonoids, alkaloids, and quinones obtained from herbs or foods. Moreover, the structure - activity correlations according to the IC50 (or Ki) values reported in the literature as well as the underlying mechanisms based on metabolic activation are highlighted in depth.
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Affiliation(s)
- Tingting Zhang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China.,Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Jinqiu Rao
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China.,Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Wei Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China.,Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
| | - Kai Wang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Feng Qiu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China.,Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
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18
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Sadeghi SJ, Di Nardo G, Gilardi G. Chimeric cytochrome P450 3A4 used for in vitro prediction of food-drug interactions. Biotechnol Appl Biochem 2020; 67:541-548. [PMID: 32713008 DOI: 10.1002/bab.1993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 07/18/2020] [Indexed: 12/26/2022]
Abstract
Inhibition of cytochrome P450 (CYP)-mediated drug metabolism by dietary substances is the main cause of drug-food interactions in humans. The present study reports on the in vitro inhibition assays of human CYP3A4 genetically linked to the reductase domain of bacterial BM3 of Bacillus megaterium (BMR) resulting in the chimeric protein CYP3A4-BMR. The activity of this chimeric enzyme was initially measured colorimetrically with erythromycin as the substrate where KM values similar to published data were determined. Subsequently, the inhibition assays with three different dietary products, grapefruit juice, curcumin, and resveratrol, were carried out with the chimeric enzyme both in solution and immobilized on electrode surfaces. For the solution studies, nicotinamide adenine dinucleotide phosphate was added as the electron donor, whereas the need for this cofactor was obviated in the immobilized enzyme as it was supplied by the electrode. Inhibition of the N-demethylation of erythromycin by CYP3A4-BMR chimera was measured at increasing concentrations of the different dietary compounds with calculated IC50 values of 0.5%, 31 μM, and 250 μM for grapefruit juice, curcumin, and resveratrol measured in solution compared with 0.7%, 24 μM, and 208 μM measured electrochemically, respectively. These data demonstrate the feasibility of the use of both CYP3A4-BMR chimera as well as bioelectrochemistry for in vitro studies of not only drug-food interactions but also prediction of adverse drug reactions in this important P450 enzyme.
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Affiliation(s)
- Sheila J Sadeghi
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.,Centre for Nanostructured Interfaces and Surfaces, University of Torino, Torino, Italy
| | - Giovanna Di Nardo
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Gianfranco Gilardi
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.,Centre for Nanostructured Interfaces and Surfaces, University of Torino, Torino, Italy
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19
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Boccanegra B, Verhaart IEC, Cappellari O, Vroom E, De Luca A. Safety issues and harmful pharmacological interactions of nutritional supplements in Duchenne muscular dystrophy: considerations for Standard of Care and emerging virus outbreaks. Pharmacol Res 2020; 158:104917. [PMID: 32485610 PMCID: PMC7261230 DOI: 10.1016/j.phrs.2020.104917] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/08/2020] [Accepted: 05/08/2020] [Indexed: 12/13/2022]
Abstract
At the moment, little treatment options are available for Duchenne muscular dystrophy (DMD). The absence of the dystrophin protein leads to a complex cascade of pathogenic events in myofibres, including chronic inflammation and oxidative stress as well as altered metabolism. The attention towards dietary supplements in DMD is rapidly increasing, with the aim to counteract pathology-related alteration in nutrient intake, the consequences of catabolic distress or to enhance the immunological response of patients as nowadays for the COVID-19 pandemic emergency. By definition, supplements do not exert therapeutic actions, although a great confusion may arise in daily life by the improper distinction between supplements and therapeutic compounds. For most supplements, little research has been done and little evidence is available concerning their effects in DMD as well as their preventing actions against infections. Often these are not prescribed by clinicians and patients/caregivers do not discuss the use with their clinical team. Then, little is known about the real extent of supplement use in DMD patients. It is mistakenly assumed that, since compounds are of natural origin, if a supplement is not effective, it will also do no harm. However, supplements can have serious side effects and also have harmful interactions, in terms of reducing efficacy or leading to toxicity, with other therapies. It is therefore pivotal to shed light on this unclear scenario for the sake of patients. This review discusses the supplements mostly used by DMD patients, focusing on their potential toxicity, due to a variety of mechanisms including pharmacodynamic or pharmacokinetic interactions and contaminations, as well as on reports of adverse events. This overview underlines the need for caution in uncontrolled use of dietary supplements in fragile populations such as DMD patients. A culture of appropriate use has to be implemented between clinicians and patients' groups.
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Affiliation(s)
- Brigida Boccanegra
- Unit of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari Aldo Moro, Bari, Italy
| | - Ingrid E C Verhaart
- Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Duchenne Parent Project, the Netherlands
| | - Ornella Cappellari
- Unit of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari Aldo Moro, Bari, Italy
| | - Elizabeth Vroom
- Duchenne Parent Project, the Netherlands; World Duchenne Organisation (UPPMD), the Netherlands
| | - Annamaria De Luca
- Unit of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari Aldo Moro, Bari, Italy.
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20
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Surendran S, Sapkal R, Paul D, Nanjappan S. Effect of resveratrol on dipeptidyl peptidase-4 inhibitors pharmacokinetics: An in vitro and in vivo approach. Chem Biol Interact 2019; 315:108909. [PMID: 31786186 DOI: 10.1016/j.cbi.2019.108909] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 11/06/2019] [Accepted: 11/25/2019] [Indexed: 12/26/2022]
Abstract
Diabetes mellitus (DM) is a metabolic disorder with hyperglycemia being its hallmark symptom. The secondary symptom of DM is oxidative stress, which leads to the generation of free radicals. Diabetic nephropathy and neuropathy is the long-term effect of oxidative stress caused in DM, which leads to damage of kidneys and neurons respectively. Resveratrol (RES) is a phytochemical, found to be effective in the treatment of diabetic nephropathy and neuropathy. Due to its antioxidant property, it reduces the oxidative stress caused by DM. Dipeptidyl peptidase-4 (DPP-4) inhibitors are used for the treatment of type 2 DM. In vitro and in vivo data depicted that the metabolism of alogliptin (ALO), saxagliptin (SAX) and sitagliptin (SIT) were decreased in presence of RES while metabolism of teneligliptin (TEN) was not affected in presence of RES. The results show that the alteration of the pharmacokinetics of ALO, SAX and SIT was due to inhibition of CYP P450 by RES. Thus, there was a significant pharmacokinetic interaction between RES-ALO, RES-SAX and RES-SIT. Hence, a dose reduction is required when RES therapy is taken in combination with ALO, SAX and SIT as there is an increase in drug exposure, which might lead to toxicity.
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Affiliation(s)
- Shruti Surendran
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Rekha Sapkal
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - David Paul
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Satheeshkumar Nanjappan
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
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21
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Wen J, Bao SS, Zhang BW, Liu TH, Ou-Yang QG, Cai JP, Zhou HY. Inhibitory effect of resveratrol on the pharmacokinetic of ibrutinib by UPLC-MS/MS. Drug Dev Ind Pharm 2019; 45:27-31. [PMID: 30156133 DOI: 10.1080/03639045.2018.1514044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To investigate the impact of resveratrol on the metabolism of ibrutinib in vitro and in vivo. METHODS In vitro, rat liver microsomes (RLM) and human liver microsomes (HLM) were used to study. In vivo, 18 male SD rats were randomly divided into three groups (n = 6): ibrutinib and the multiple dose of 100 mg/kg resveratrol for consecutive 7 days (Group A), ibrutinib and the single dose of 100 mg/kg resveratrol (Group B), ibrutinib (Group C). Processed samples were analyzed by UPLC-MS/MS. RESULTS Resveratrol showed inhibition on RLM and HLM in vitro. The IC50 of resveratrol was 8.745 µM in RLM and 7.789 µM in HLM. Furthermore, Groups A and B both increased the AUC and reduced the CLz/F. The Cmax of Group A and the MRT(0-t) of Group B were significantly improved. CONCLUSIONS Resveratrol inhibits the pharmacokinetic of ibrutinib in vitro and in vivo. It is necessary to pay more attention to adjust the dose of the drug when resveratrol is used in combination with ibrutinib.
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Affiliation(s)
- Jian Wen
- a School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Su-Su Bao
- a School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Bo-Wen Zhang
- a School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Teng-Hui Liu
- a School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Qiu-Geng Ou-Yang
- a School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Jian-Ping Cai
- a School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Hong-Yu Zhou
- a School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
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Alamo A, Condorelli RA, Mongioì LM, Cannarella R, Giacone F, Calabrese V, La Vignera S, Calogero AE. Environment and Male Fertility: Effects of Benzo-α-Pyrene and Resveratrol on Human Sperm Function In Vitro. J Clin Med 2019; 8:jcm8040561. [PMID: 31027257 PMCID: PMC6518055 DOI: 10.3390/jcm8040561] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 04/12/2019] [Accepted: 04/19/2019] [Indexed: 12/13/2022] Open
Abstract
Lifestyle, cigarette smoking and environmental pollution have a negative impact on male fertility. Therefore, the aim of this study was to evaluate the in-vitro effects of benzo-α-pyrene (BaP) and aryl hydrocarbon receptor (AHR) agonists on motility and bio-functional sperm parameters. We further assessed whether resveratrol (RES), an AHR antagonist and antioxidant molecule, had any protective effect. To accomplish this, 30 normozoospermic, healthy, non-smoker men not exposed to BaP were enrolled. Spermatozoa of 15 men were incubated with increasing concentrations of BaP to evaluate its effect and to establish its dose response. Then, spermatozoa of the 15 other men were incubated with BaP (15 µM/mL), chosen according to the dose-response and/or RES to evaluate its antagonistic effects. The effects of both substances were evaluated after 3 h of incubation on total and progressive sperm motility and on the following bio-functional sperm parameters evaluated by flow cytometry: Degree of chromatin compactness, viability, phosphatidylserine externalization (PS), late apoptosis, mitochondrial membrane potential (MMP), DNA fragmentation, degree of lipoperoxidation (LP), and concentrations of mitochondrial superoxide anion. Benzo-α-pyrene decreased total and progressive sperm motility, impaired chromatin compactness, and increased sperm lipoperoxidation and mitochondrial superoxide anion levels. All these effects were statistically significant at the lowest concentration tested (15 µM/mL) and they were confirmed at the concentration of 45 µM/mL. In turn, RES was able to counteract the detrimental effects of BaP on sperm motility, abnormal chromatin compactness, lipid peroxidation, and mitochondrial superoxide. This study showed that BaP alters sperm motility and bio-functional sperm parameters and that RES exerts a protective effect on BaP-induced sperm damage.
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Affiliation(s)
- Angela Alamo
- Department of Clinical and Experimental Medicine, 95123 Catania, Italy.
| | | | - Laura M Mongioì
- Department of Clinical and Experimental Medicine, 95123 Catania, Italy.
| | | | - Filippo Giacone
- Department of Clinical and Experimental Medicine, 95123 Catania, Italy.
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, 95123 Catania, Italy.
| | - Sandro La Vignera
- Department of Clinical and Experimental Medicine, 95123 Catania, Italy.
- CoHEAR, Research Center for Smoking Damage Reduction, University of Catania, 95123 Catania, Italy.
| | - Aldo E Calogero
- Department of Clinical and Experimental Medicine, 95123 Catania, Italy.
- CoHEAR, Research Center for Smoking Damage Reduction, University of Catania, 95123 Catania, Italy.
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Abouzeid S, Beutling U, Selmar D. Stress-induced modification of indole alkaloids:Phytomodificines as a new category of specialized metabolites. PHYTOCHEMISTRY 2019; 159:102-107. [PMID: 30605851 DOI: 10.1016/j.phytochem.2018.12.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/19/2018] [Accepted: 12/22/2018] [Indexed: 06/09/2023]
Abstract
This study focuses on the elucidation of the stress-induced reverse changes of major indole alkaloids in Vinca minor, primarily on the postulated conversion of vincamine and vincadifformine to yield 9-methoxyvincamine, minovincine, and minovincinine, respectively. By applying the P450 enzyme inhibitors, naproxen and resveratrol, it was shown that the oxidative reaction involved in the postulated conversion of vincamine and vincadifformine is catalyzed by cytochrome P450 enzymes. In combination with the identification of 9-hydroxyvincamine as a postulated intermediate, this result confirms that the observed stress-induced reverse changes in the alkaloid pattern are caused by modifications of the alkaloids which regularly accumulate in the healthy Vinca minor plants. Up to now, just two main types of defense compounds are distinguished: phytoalexins, which are synthesized de novo from primary metabolites and phytoanticipins, which are constitutively present in plants - either intrinsically active or are activated after cell death by hydrolysis or oxidation of the precursors. In contrast, the results presented in this paper demonstrate that indole alkaloids, representing typical phytoanticipins, are just slightly modified in response to a stress-related elicitation. Accordingly, these modified alkaloids neither represent classical phytoalexins (being synthesized de novo), nor can they be classified as phytoanticipins, since modification does not occur postmortem. Consequently, we propose a new category for these modified alkaloids that we call phytomodificines.
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Affiliation(s)
- Sara Abouzeid
- Institute for Plant Biology, TU Braunschweig, Mendelssohnsstr. 4, 38106, Braunschweig, Germany; Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Ulrike Beutling
- Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstraße7, 38124, Braunschweig, Germany
| | - Dirk Selmar
- Institute for Plant Biology, TU Braunschweig, Mendelssohnsstr. 4, 38106, Braunschweig, Germany.
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Tan-Koi WC, Limenta M, Mohamed EHM, Lee EJD. The Importance of Ethnicity Definitions and Pharmacogenomics in Ethnobridging and Pharmacovigilance. Pharmacogenomics 2019. [DOI: 10.1016/b978-0-12-812626-4.00011-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles. Pharmaceutics 2018; 10:pharmaceutics10040277. [PMID: 30558213 PMCID: PMC6321138 DOI: 10.3390/pharmaceutics10040277] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 11/29/2018] [Accepted: 12/13/2018] [Indexed: 12/24/2022] Open
Abstract
Preclinical and clinical studies suggest that many food molecules could interact with drug transporters and metabolizing enzymes through different mechanisms, which are predictive of what would be observed clinically. Given the recent incorporation of dietary modifications or supplements in traditional medicine, an increase in potential food-drug interactions has also appeared. The objective of this article is to review data regarding the influence of food on drug efficacy. Data from Google Scholar, PubMed, and Scopus databases was reviewed for publications on pharmaceutical, pharmacokinetic, and pharmacodynamic mechanisms. The following online resources were used to integrate functional and bioinformatic results: FooDB, Phenol-Explorer, Dr. Duke's Phytochemical and Ethnobotanical Databases, DrugBank, UniProt, and IUPHAR/BPS Guide to Pharmacology. A wide range of food compounds were shown to interact with proteins involved in drug pharmacokinetic/pharmacodynamic profiles, starting from drug oral bioavailability to enteric/hepatic transport and metabolism, blood transport, and systemic transport/metabolism. Knowledge of any food components that may interfere with drug efficacy is essential, and would provide a link for obtaining a holistic view for cancer, cardiovascular, musculoskeletal, or neurological therapies. However, preclinical interaction may be irrelevant to clinical interaction, and health professionals should be aware of the limitations if they intend to optimize the therapeutic effects of drugs.
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Ghosh J, Chowdhury AR, Srinivasan S, Chattopadhyay M, Bose M, Bhattacharya S, Raza H, Fuchs SY, Rustgi AK, Gonzalez FJ, Avadhani NG. Cigarette Smoke Toxins-Induced Mitochondrial Dysfunction and Pancreatitis Involves Aryl Hydrocarbon Receptor Mediated Cyp1 Gene Expression: Protective Effects of Resveratrol. Toxicol Sci 2018; 166:428-440. [PMID: 30165701 PMCID: PMC6260170 DOI: 10.1093/toxsci/kfy206] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
We previously reported that mitochondrial CYP1 enzymes participate in the metabolism of polycyclic aromatic hydrocarbons and other carcinogens leading to mitochondrial dysfunction. In this study, using Cyp1b1-/-, Cyp1a1/1a2-/-, and Cyp1a1/1a2/1b1-/- mice, we observed that cigarette and environmental toxins, namely benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induce pancreatic mitochondrial respiratory dysfunction and pancreatitis. Our results suggest that aryl hydrocarbon receptor (AhR) activation and resultant mitochondrial dysfunction are associated with pancreatic pathology. BaP treatment markedly inhibits pancreatic mitochondrial oxygen consumption rate (OCR), ADP-dependent OCR, and also maximal respiration, in wild-type mice but not in Cyp1a1/1a2-/- and Cyp1a1/1a2/1b1-/- mice. In addition, both BaP and TCDD treatment markedly affected mitochondrial complex IV activity, in addition to causing marked reduction in mitochondrial DNA content. Interestingly, the AhR antagonist resveratrol, attenuated BaP-induced mitochondrial respiratory defects in the pancreas, and reversed pancreatitis, both histologically and biochemically in wild-type mice. These results reveal a novel role for AhR- and AhR-regulated CYP1 enzymes in eliciting mitochondrial dysfunction and cigarette toxin-mediated pancreatic pathology. We propose that increased mitochondrial respiratory dysfunction and oxidative stress are involved in polycyclic aromatic hydrocarbon associated pancreatitis. Resveratrol, a chemo preventive agent and AhR antagonist, and CH-223191, a potent and specific AhR inhibitor, confer protection against BaP-induced mitochondrial dysfunction and pancreatic pathology.
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Affiliation(s)
- Jyotirmoy Ghosh
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- Department of Chemistry, Banwarilal Bhalotia College, Asansol, Ushagram, Asansol-713303, West Bengal, India
| | - Anindya Roy Chowdhury
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Satish Srinivasan
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- Roche Molecular Systems, 1080, US-202, Branchburg, NJ 08876
| | - Mrittika Chattopadhyay
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Moumita Bose
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390
| | - Sabyasachi Bhattacharya
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426
| | - Haider Raza
- Department of Biochemistry, College of Medicine and Health Sciences, UAE University, Al-Ain, UAE
| | - Serge Y Fuchs
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Anil K Rustgi
- Division of Gastroenterology, Departments of Medicine and Genetics, and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Frank J Gonzalez
- National Cancer Institute, Center for Cancer Research, Bethesda, Maryland 20892
| | - Narayan G Avadhani
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Mohos V, Bencsik T, Boda G, Fliszár-Nyúl E, Lemli B, Kunsági-Máté S, Poór M. Interactions of casticin, ipriflavone, and resveratrol with serum albumin and their inhibitory effects on CYP2C9 and CYP3A4 enzymes. Biomed Pharmacother 2018; 107:777-784. [DOI: 10.1016/j.biopha.2018.08.068] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/15/2018] [Accepted: 08/15/2018] [Indexed: 01/17/2023] Open
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Hyrsova L, Vanduchova A, Dusek J, Smutny T, Carazo A, Maresova V, Trejtnar F, Barta P, Anzenbacher P, Dvorak Z, Pavek P. Trans-resveratrol, but not other natural stilbenes occurring in food, carries the risk of drug-food interaction via inhibition of cytochrome P450 enzymes or interaction with xenosensor receptors. Toxicol Lett 2018; 300:81-91. [PMID: 30394306 DOI: 10.1016/j.toxlet.2018.10.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 09/03/2018] [Accepted: 10/08/2018] [Indexed: 01/27/2023]
Abstract
Resveratrol (RSV) is a stilbene phytochemical common in food and red wine. RSV inhibits cytochrome P450 CYP3A4 activity and interacts with the pregnane X receptor (PXR), the central regulator of drug/xenobiotic metabolizing enzyme expression. In this work, we comprehensively examined the effects of 13 stilbenes (trans- and cis-resveratrol, trans- and cis-piceatannol, oxyresveratrol, pterostilbene, pinostilbene, a,b-dihydroresveratrol, trans- and cis-trismethoxyresveratrol, trans-3,4,5,4'-tetramethoxystilbene, trans-2,4,3',5'-tetramethoxystilbene, trans-4-methoxystilbene), on CYP3A4 and CYP2B6 mRNA induction, and on CYP3A4/5, CYP2C8/9/19, CYP2D6, CYP2A6, CYP2E1, CYP1A2 and CYP2B6 cytochrome P450 enzyme activities. Expression experiments in five different primary human hepatocyte preparations, reporter gene assays, and ligand binding assays with pregnane X (PXR) and constitutive androstane (CAR) receptors were performed. Inhibition of cytochrome P450 enzymes was examined in human microsomes. We found that only polymethoxylated stilbenes are prone to significantly induce CYP2B6 or CYP3A4 in primary human hepatocytes via pregnane X receptor (PXR) interaction. Natural resveratrol derivatives such as trans- and cis-RSV, oxyresveratrol, pinostilbene and pterostilbene significantly inhibit CYP3A4/5 enzymatic activities; however, only trans-RSV significantly inhibits CYP3A4/5 activity (both testosterone 6β-hydroxylation and midazolam 1´-hydroxylation) in micromolar concentrations by a non-competitive mechanism, suggesting a potential risk of food-drug interactions with CYP3A4/5 substrates.
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Affiliation(s)
- Lucie Hyrsova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic
| | - Alena Vanduchova
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 3, CZ775 15, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine (IMTM), Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 3, CZ775 15, Olomouc, Czech Republic
| | - Jan Dusek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic
| | - Tomas Smutny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic
| | - Alejandro Carazo
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic; Institute of Molecular and Translational Medicine (IMTM), Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 3, CZ775 15, Olomouc, Czech Republic
| | - Veronika Maresova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic
| | - Frantisek Trejtnar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic
| | - Pavel Barta
- Department of Biophysics and Physical Chemistry, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic
| | - Pavel Anzenbacher
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 3, CZ775 15, Olomouc, Czech Republic
| | - Zdenek Dvorak
- Department of Cellular Biology and Genetics, Faculty of Sciences, Palacky University in Olomouc, Slechtitelu 27, 783 71, Olomouc, Czech Republic
| | - Petr Pavek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic.
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29
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Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, Fokou PVT, Martins N, Sharifi-Rad J. Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines 2018; 6:E91. [PMID: 30205595 PMCID: PMC6164842 DOI: 10.3390/biomedicines6030091] [Citation(s) in RCA: 608] [Impact Index Per Article: 86.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 09/03/2018] [Accepted: 09/07/2018] [Indexed: 12/18/2022] Open
Abstract
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) belongs to polyphenols' stilbenoids group, possessing two phenol rings linked to each other by an ethylene bridge. This natural polyphenol has been detected in more than 70 plant species, especially in grapes' skin and seeds, and was found in discrete amounts in red wines and various human foods. It is a phytoalexin that acts against pathogens, including bacteria and fungi. As a natural food ingredient, numerous studies have demonstrated that resveratrol possesses a very high antioxidant potential. Resveratrol also exhibit antitumor activity, and is considered a potential candidate for prevention and treatment of several types of cancer. Indeed, resveratrol anticancer properties have been confirmed by many in vitro and in vivo studies, which shows that resveratrol is able to inhibit all carcinogenesis stages (e.g., initiation, promotion and progression). Even more, other bioactive effects, namely as anti-inflammatory, anticarcinogenic, cardioprotective, vasorelaxant, phytoestrogenic and neuroprotective have also been reported. Nonetheless, resveratrol application is still being a major challenge for pharmaceutical industry, due to its poor solubility and bioavailability, as well as adverse effects. In this sense, this review summarized current data on resveratrol pharmacological effects.
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Affiliation(s)
- Bahare Salehi
- Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran 88777539, Iran.
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran 22439789, Iran.
| | - Abhay Prakash Mishra
- Department of Pharmaceutical Chemistry, H. N. B. Garhwal (A Central) University, Srinagar Garhwal 246174, Uttarakhand, India.
| | - Manisha Nigam
- Department of Biochemistry, H. N. B. Garhwal (A Central) University, Srinagar Garhwal 246174, Uttarakhand, India.
| | - Bilge Sener
- Gazi University Faculty of Pharmacy Department of Pharmacognosy, Ankara 06330, Turkey.
| | - Mehtap Kilic
- Gazi University Faculty of Pharmacy Department of Pharmacognosy, Ankara 06330, Turkey.
| | - Mehdi Sharifi-Rad
- Department of Medical Parasitology, Zabol University of Medical Sciences, Zabol 61663335, Iran.
| | - Patrick Valere Tsouh Fokou
- Antimicrobial and Biocontrol Agents Unit, Department of Biochemistry, Faculty of Science, University of Yaounde 1, Ngoa Ekelle, Annex Fac. Sci, P.O. Box. 812, Yaounde-Cameroon.
| | - Natália Martins
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto 4200-319, Portugal.
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto 4200-135, Portugal.
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran 11369, Iran.
- Department of Chemistry, Richardson College for the Environmental Science Complex, The University of Winnipeg, Winnipeg, MB R3B 2G3, Canada.
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30
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Elshaer M, Chen Y, Wang XJ, Tang X. Resveratrol: An overview of its anti-cancer mechanisms. Life Sci 2018; 207:340-349. [DOI: 10.1016/j.lfs.2018.06.028] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/21/2018] [Accepted: 06/25/2018] [Indexed: 02/07/2023]
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N'guessan BB, Amponsah SK, Dugbartey GJ, Awuah KD, Dotse E, Aning A, Kukuia KKE, Asiedu-Gyekye IJ, Appiah-Opong R. In Vitro Antioxidant Potential and Effect of a Glutathione-Enhancer Dietary Supplement on Selected Rat Liver Cytochrome P450 Enzyme Activity. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:7462839. [PMID: 29977317 PMCID: PMC5994258 DOI: 10.1155/2018/7462839] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/03/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND There is considerable evidence that many people take dietary supplements including those of herbal origin as an alternative therapy to improve their health. One such supplement, with an amalgam of constituents, is CellGevity®. However, the effect of this dietary supplement on drug-metabolizing enzymes is poorly understood, as it has not been studied extensively. Therefore, we investigated the effect of CellGevity dietary supplement on selected rat liver microsomal cytochrome P450 (CYP) enzymes, the most common drug-metabolizing enzymes. We also determined the total antioxidant potential of this dietary supplement in vitro. METHODS To determine the antioxidant potential of CellGevity dietary supplement, 2,2-diphenyl-2-picryl-hydrazyl (DPPH), total phenolic, and flavonoid assays were used after initial preparation of a solution form of the supplement (low dose, LD; 4 mg/kg and high dose, HD; 8 mg/kg). Rats received oral administration of these doses of the supplement for 7 days, after which the effect of the supplement on selected liver CYP enzymes was assessed using probe substrates and spectroscopic and high-performance liquid chromatographic methods. Rats which received daily administration of 80 mg/kg of phenobarbitone and distilled water served as positive and negative controls, respectively. RESULTS The IC50 value of the supplement 0.34 ± 0.07 mg/ml compared to 0.076 ± 0.03 mg/ml of the BHT (positive control). The total phenolic content of the supplement at a concentration of 2.5 mg/ml was 34.97 g gallic acid equivalent (GAE)/100 g while its total flavonoid content at a concentration of 2.5 mg/ml was 6 g quercetin equivalent (QE)/100 g. The supplement significantly inhibited rat CYP2B1/2B2 (LDT 92.4%; HDT 100%), CYP3A4 (LDT 81.2%; HDT 71.7%), and CYP2C9 (LDT 21.7%; HDT 28.5%) while it had no significant inhibitory effect on CYPs 1A1/1A2, CYP1A2, and CYP2D6. CONCLUSION CellGevity dietary supplement possesses moderate antioxidant activity in vitro and has an inhibitory effect on selected rat liver CYP enzymes, suggesting its potential interaction with drugs metabolized by CYP enzymes.
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Affiliation(s)
- Benoit B. N'guessan
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Ghana
| | - Seth K. Amponsah
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Ghana
| | - George J. Dugbartey
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Ghana
| | - Kwabena D. Awuah
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Ghana
| | - Eunice Dotse
- Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Ghana
| | - Abigail Aning
- Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Ghana
| | - Kennedy K. E. Kukuia
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Ghana
| | - Isaac J. Asiedu-Gyekye
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Ghana
| | - Regina Appiah-Opong
- Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Ghana
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Hosogi J, Ohashi R, Maeda H, Fujita K, Ushiki J, Kuwabara T, Yamamoto Y, Imamura T. An iminium ion metabolite hampers the production of the pharmacologically active metabolite of a multikinase inhibitor KW-2449 in primates: irreversible inhibition of aldehyde oxidase and covalent binding with endogenous proteins. Biopharm Drug Dispos 2018; 39:164-174. [DOI: 10.1002/bdd.2123] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 02/01/2018] [Accepted: 02/06/2018] [Indexed: 02/05/2023]
Affiliation(s)
- Jun Hosogi
- Translational Research Unit; Research and Development Division, Kyowa Hakko Kirin Co., Ltd; 1188 Shimotogari, Nagaizumi-cho, Sunto-gun Shizuoka 411-8731 Japan
| | - Rui Ohashi
- Translational Research Unit; Research and Development Division, Kyowa Hakko Kirin Co., Ltd; 1188 Shimotogari, Nagaizumi-cho, Sunto-gun Shizuoka 411-8731 Japan
| | - Hiroshi Maeda
- Translational Research Unit; Research and Development Division, Kyowa Hakko Kirin Co., Ltd; 1188 Shimotogari, Nagaizumi-cho, Sunto-gun Shizuoka 411-8731 Japan
| | - Kazuhiro Fujita
- Translational Research Unit; Research and Development Division, Kyowa Hakko Kirin Co., Ltd; 1188 Shimotogari, Nagaizumi-cho, Sunto-gun Shizuoka 411-8731 Japan
| | - Junko Ushiki
- Translational Research Unit; Research and Development Division, Kyowa Hakko Kirin Co., Ltd; 1188 Shimotogari, Nagaizumi-cho, Sunto-gun Shizuoka 411-8731 Japan
| | - Takashi Kuwabara
- Translational Research Unit; Research and Development Division, Kyowa Hakko Kirin Co., Ltd; 1188 Shimotogari, Nagaizumi-cho, Sunto-gun Shizuoka 411-8731 Japan
| | - Yorihiro Yamamoto
- School of Bioscience and Biotechnology; Tokyo University of Technology; 1404-1 Katakura-cho, Hachioji Tokyo 192-0983 Japan
| | - Toru Imamura
- School of Bioscience and Biotechnology; Tokyo University of Technology; 1404-1 Katakura-cho, Hachioji Tokyo 192-0983 Japan
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Cancer chemoprevention revisited: Cytochrome P450 family 1B1 as a target in the tumor and the microenvironment. Cancer Treat Rev 2017; 63:1-18. [PMID: 29197745 DOI: 10.1016/j.ctrv.2017.10.013] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/30/2017] [Accepted: 10/31/2017] [Indexed: 02/08/2023]
Abstract
Cancer chemoprevention is the use of synthetic, natural or biological agents to prevent or delay the development or progression of malignancies. Intriguingly, many phytochemicals with anti-inflammatory and anti-angiogenic effects, recently proposed as chemoprevention strategies, are inhibitors of Cytochrome P450 family 1B1 (CYP1B1), an enzyme overexpressed in a wide variety of tumors and associated with angiogenesis. In turn, pro-inflammatory cytokines were reported to boost CYP1B1 expression, suggesting a key role of CYP1B1 in a positive loop of inflammatory angiogenesis. Other well-known pro-tumorigenic activities of CYP1B1 rely on metabolic bioactivation of xenobiotics and steroid hormones into their carcinogenic derivatives. In contrast to initial in vitro observations, in vivo studies demonstrated a protecting role against cancer for the other CYP1 family members (CYP1A1 and CYP1A2), suggesting that the specificity of CYP1 family inhibitors should be carefully taken into account for developing potential chemoprevention strategies. Recent studies also proposed a role of CYP1B1 in multiple cell types found within the tumor microenvironment, including fibroblasts, endothelial and immune cells. Overall, our review of the current literature suggests a positive loop between inflammatory cytokines and CYP1B1, which in turn may play a key role in cancer angiogenesis, acting on both cancer cells and the tumor microenvironment. Strategies aiming at specific CYP1B1 inhibition in multiple cell types may translate into clinical chemoprevention and angioprevention approaches.
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β-Naphthoflavone-Induced Mitochondrial Respiratory Damage in Cyp1 Knockout Mouse and in Cell Culture Systems: Attenuation by Resveratrol Treatment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:5213186. [PMID: 29098061 PMCID: PMC5618780 DOI: 10.1155/2017/5213186] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 08/15/2017] [Indexed: 12/21/2022]
Abstract
A number of xenobiotic-inducible cytochrome P450s (CYPs) are now known to be localized in the mitochondrial compartment, though their pharmacological or toxicological roles remain unclear. Here, we show that BNF treatment markedly inhibits liver mitochondrial O2 consumption rate (OCR), ADP-dependent OCR, and also reserve OCR, in wild-type mice but not in Cyp1a1/1a2(-/-) double knockout mice. BNF treatment markedly affected mitochondrial complex I and complex IV activities and also attenuated mitochondrial gene expression. Furthermore, under in vitro conditions, BNF treatment induced cellular ROS production, which was inhibited by mitochondria-targeted antioxidant Mito-CP and CYP inhibitor proadefin, suggesting that most of the ROS production was intramitochondrial and probably involved the catalytic activity of mitochondrial CYP1 enzymes. Interestingly, our results also show that the AHR antagonist resveratrol, markedly attenuated BNF-induced liver mitochondrial defects in wild-type mice, confirming the role of AHR and AHR-regulated CYP1 genes in eliciting mitochondrial dysfunction. These results are consistent with reduced BNF-induced mitochondrial toxicity in Cyp1a1/1a2(-/-) mice and elevated ROS production in COS cells stably expressing CYP1A1. We propose that increased mitochondrial ROS production and respiratory dysfunction are part of xenobiotic toxicity. Resveratrol, a chemopreventive agent, renders protection against BNF-induced toxicity.
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Basheer L, Schultz K, Guttman Y, Kerem Z. In silico and in vitro inhibition of cytochrome P450 3A by synthetic stilbenoids. Food Chem 2017; 237:895-903. [PMID: 28764083 DOI: 10.1016/j.foodchem.2017.06.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 05/07/2017] [Accepted: 06/06/2017] [Indexed: 01/19/2023]
Abstract
Inhibition of cytochrome P450 3A4 (CYP3A4), the major drug metabolizing enzyme, by dietary compounds has recently attracted increased attention. Evaluating the potency of the many known inhibitory compounds is a tedious and time consuming task, yet it can be achieved using computing tools. Here, CDOCKER and Glide served to design model inhibitors in order to characterize molecular features of an inhibitor. Assessing nitro-stilbenoids, both approaches suggested nitrostilbene to be a weaker inhibitor of CYP3A4 than resveratrol, and stronger than dimethoxy-nitrostilbene. Nitrostilbene and resveratrol, but not dimethoxy-nitrostilbene, engage electrostatic interactions in the enzyme cavity, and with the haem. In vitro assessment of the inhibitory capacity supported the in silico predictions, suggesting that evaluating the electrostatic interactions of a compound with the prosthetic group allows the prediction of inhibitory potency. Since both programs yielded related results, it is suggested that for CYP3A4, computing tools may allow rapid identification of potent dietary inhibitors.
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Affiliation(s)
- Loai Basheer
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
| | - Keren Schultz
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
| | - Yelena Guttman
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
| | - Zohar Kerem
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
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Liu R, Tam TW, Mao J, Salem A, Arnason JT, Krantis A, Foster BC. In vitro activity of Lycium barbarum (Goji) against major human phase I metabolism enzymes. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2017; 13:257-265. [PMID: 27352447 DOI: 10.1515/jcim-2015-0038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 05/15/2016] [Indexed: 11/15/2022]
Abstract
BACKGROUND Goji berry (Lycium barbarum) has been used as traditional Chinese medicine and a functional food in China. Goji tea may interact with drugs such as warfarin by inhibiting the cytochrome P450 (CYP) 2C9, and this study was undertaken to characterize the effect of Goji products on CYP2C9/19-, CYP2D6 *1/*10-, CYP3A4/5/7-, CYP19-, and flavin-containing monooxygenase (FMO) 3-mediated metabolism. METHODS Goji juice, water, and ethanol extracts were examined for their effect on CYP2C9/19-, 2D6-, 3A4/5/7-, 4A11-, CYP19-, and FMO3-mediated metabolism by using in vitro bioassay. The mechanism-based inactivation (MBI) of Goji juice on CYP3A4 was also examined. RESULTS Data indicates that both fresh juice and commercially available juice caused strong inhibition (over 75 %) of most of the major CYP450 enzymes and moderate inhibition of FMO3 (30-60 %). Compared to juice, the Goji cold/hot water extracts effected low inhibition (below 30 %) of these enzymes. Ethanol (80 %) extracts exhibit the strongest inhibition on CYP2C9 and 2C19 (over 90 %). The inhibition pattern of dried and fresh berry extract and high-performance liquid chromatography (HPLC)-UV fingerprints were similar. CONCLUSIONS These findings suggest that Goji products (berries, tea, tincture, and juice) can inhibit phase I drug metabolism enzymes and have the potential to affect the safety and efficacy of therapeutic products.
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Zamaratskaia G, Thøgersen R, Čandek-Potokar M, Rasmussen MK. Co-treatment with indole-3-carbinol and resveratrol modify porcine CYP1A and CYP3A activities and expression. Xenobiotica 2017; 48:232-240. [DOI: 10.1080/00498254.2017.1300708] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Galia Zamaratskaia
- Department of Molecular Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden,
- Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, University of South Bohemia in Ceske Budejovice, Vodnany, Czech Republic,
| | | | - Marjeta Čandek-Potokar
- Agricultural Institute of Slovenia, Ljubljana, Slovenia, and
- Faculty of Agriculture and Life Sciences, University of Maribor, Hoče, Slovenia
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Rühlmann A, Antovic D, Müller TJJ, Urlacher VB. Regioselective Hydroxylation of Stilbenes by Engineered Cytochrome P450 fromThermobifida fuscaYX. Adv Synth Catal 2017. [DOI: 10.1002/adsc.201601168] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Ansgar Rühlmann
- Institute of Biochemistry; Heinrich-Heine University Düsseldorf; Universitätsstr.1 40225 Düsseldorf Germany
| | - Dragutin Antovic
- Institute of Macromolecular and Organic Chemistry, Chair of Organic Chemistry; Heinrich-Heine University Düsseldorf; Universitätsstr. 1 40225 Düsseldorf Germany
| | - Thomas J. J. Müller
- Institute of Macromolecular and Organic Chemistry, Chair of Organic Chemistry; Heinrich-Heine University Düsseldorf; Universitätsstr. 1 40225 Düsseldorf Germany
| | - Vlada B. Urlacher
- Institute of Biochemistry; Heinrich-Heine University Düsseldorf; Universitätsstr.1 40225 Düsseldorf Germany
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Guthrie AR, Chow HS, Martinez JA. Effects of resveratrol on drug- and carcinogen-metabolizing enzymes, implications for cancer prevention. Pharmacol Res Perspect 2017; 5:e00294. [PMID: 28596842 PMCID: PMC5461649 DOI: 10.1002/prp2.294] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 10/20/2016] [Accepted: 12/12/2016] [Indexed: 12/29/2022] Open
Abstract
Resveratrol is a polyphenol found in grape skins and peanuts that has demonstrated many health benefits including protection against aging, cardiovascular and metabolic disease, neurological decline, and cancer. The anticancer properties of resveratrol have been attributed to a variety of mechanisms, including its general inhibition of phase I metabolism and induction of phase II metabolism. The effects of resveratrol on these enzymes, however, are still unclear, as in vitro evidence often contrasts with animal studies and clinical trials. Reasons for these variances could include the low bioavailability of resveratrol and the effects of resveratrol metabolites. Due to resveratrol's interactions with drug-metabolizing enzymes and drug transporters, individuals concurrently taking pharmacological doses of resveratrol with other supplements or medications could potentially experience nutrient-drug interactions. This review summarizes the known effects of resveratrol and its main metabolites on drug metabolism in order to help characterize which populations might benefit from resveratrol for the prevention of cancer, as well as those that may need to avoid supplementation due to potential drug interactions.
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Affiliation(s)
- Ariane R. Guthrie
- Department of Nutritional SciencesUniversity of ArizonaTucsonArizona
| | | | - Jessica A. Martinez
- Department of Nutritional SciencesUniversity of ArizonaTucsonArizona
- University of Arizona Cancer CenterTucsonArizona
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Ma J, Li J, Tian YS. Synthesis and bioactivity evaluation of 2,3-diaryl acrylonitrile derivatives as potential anticancer agents. Bioorg Med Chem Lett 2017; 27:81-85. [DOI: 10.1016/j.bmcl.2016.11.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 10/09/2016] [Accepted: 11/11/2016] [Indexed: 01/11/2023]
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El-Sherbeni AA, El-Kadi AOS. Microsomal cytochrome P450 as a target for drug discovery and repurposing. Drug Metab Rev 2016; 49:1-17. [DOI: 10.1080/03602532.2016.1257021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Ahmed A. El-Sherbeni
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Alberta, Canada
| | - Ayman O. S. El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Alberta, Canada
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Li J, Liu Y, Zhang J, Yu X, Wang X, Zhao L. Effects of resveratrol on P-glycoprotein and cytochrome P450 3A in vitro and on pharmacokinetics of oral saquinavir in rats. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:3699-3706. [PMID: 27895462 PMCID: PMC5117956 DOI: 10.2147/dddt.s118723] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background The intestinal cytochrome P450 3A (CYP 3A) and P-glycoprotein (P-gp) present a barrier to the oral absorption of saquinavir (SQV). Resveratrol (RESV) has been indicated to have modulatory effects on P-gp and CYP 3A. Therefore, this study was to investigate the effects of RESV on P-gp and CYP 3A activities in vitro and in vivo on oral SQV pharmacokinetics in rats. Methods In vitro, intestinal microsomes were used to evaluate RESV effect on CYP 3A-mediated metabolism of SQV; MDR1-expressing Madin–Darby canine kidney (MDCKII-MDR1) cells were employed to assess the impact of RESV on P-gp-mediated efflux of SQV. In vivo effects were studied using 10 rats randomly assigned to receive oral SQV (30 mg/kg) with or without RESV (20 mg/kg). Serial blood samples were obtained over the following 24 h. Concentrations of SQV in samples were ascertained using high-performance liquid chromatography-tandem mass spectrometry analysis. Results RESV (1–100 μM) enhanced residual SQV (% of control) in a dose-dependent manner after incubation with intestinal microsomes. RESV (1–100 μM) reduced the accumulation of SQV in MDCKII-MDR1 cells in a concentration-dependent manner. A double peaking phenomenon was observed in the plasma SQV profiles in rats. The first peak of plasma SQV concentration was increased, but the second peak was reduced by coadministration with RESV. The mean AUC0–∞ of SQV was slightly decreased, with no statistical significance probably due to the high individual variation. Conclusion RESV can alter the plasma SQV concentration profiles, shorten the Tmax of SQV. RESV might also cause a slight decrease tendency in the SQV bioavailability in rats.
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Affiliation(s)
- Jiapeng Li
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China
| | - Yang Liu
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China
| | - Jingru Zhang
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China
| | - Xiaotong Yu
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China
| | - Xiaoling Wang
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University
| | - Libo Zhao
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University
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Inhibition of cytochrome P450 3A by acetoxylated analogues of resveratrol in in vitro and in silico models. Sci Rep 2016; 6:31557. [PMID: 27530542 PMCID: PMC4987671 DOI: 10.1038/srep31557] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 07/19/2016] [Indexed: 01/05/2023] Open
Abstract
Many dietary compounds, including resveratrol, are potent inhibitors of CYP3A4. Here we examined the potential to predict inhibition capacity of dietary polyphenolics using an in silico and in vitro approaches and synthetic model compounds. Mono, di, and tri-acetoxy resveratrol were synthesized, a cell line of human intestine origin and microsomes from rat liver served to determine their in vitro inhibition of CYP3A4, and compared to that of resveratrol. Docking simulation served to predict the affinity of the synthetic model compounds to the enzyme. Modelling of the enzyme’s binding site revealed three types of interaction: hydrophobic, electrostatic and H-bonding. The simulation revealed that each of the examined acetylations of resveratrol led to the loss of important interactions of all types. Tri-acetoxy resveratrol was the weakest inhibitor in vitro despite being the more lipophilic and having the highest affinity for the binding site. The simulation demonstrated exclusion of all interactions between tri-acetoxy resveratrol and the heme due to distal binding, highlighting the complexity of the CYP3A4 binding site, which may allow simultaneous accommodation of two molecules. Finally, the use of computational modelling may serve as a quick predictive tool to identify potential harmful interactions between dietary compounds and prescribed drugs.
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Chronic acrylamide exposure in male mice induces DNA damage to spermatozoa; Potential for amelioration by resveratrol. Reprod Toxicol 2016; 63:1-12. [DOI: 10.1016/j.reprotox.2016.05.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 05/03/2016] [Accepted: 05/07/2016] [Indexed: 01/21/2023]
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Abu-Amero KK, Kondkar AA, Chalam KV. Resveratrol and Ophthalmic Diseases. Nutrients 2016; 8:200. [PMID: 27058553 PMCID: PMC4848669 DOI: 10.3390/nu8040200] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 03/25/2016] [Accepted: 03/29/2016] [Indexed: 11/16/2022] Open
Abstract
Resveratrol, a naturally occurring plant polyphenol found in grapes, is the principal biologically active component in red wine. Clinical studies have shown that resveratrol due to its potent anti-oxidant and anti-inflammatory properties are cardio-protective, chemotherapeutic, neuroprotective, and display anti-aging effects. Oxidative stress and inflammation play a critical role in the initiation and progression of age-related ocular diseases (glaucoma, cataract, diabetic retinopathy and macular degeneration) that lead to progressive loss of vision and blindness. In vitro and in vivo (animal model) experimental studies performed so far have provided evidence for the biological effects of resveratrol on numerous pathways including oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, pro-survival or angiogenesis that are implicated in the pathogenesis of these age-related ocular disorders. In this review, we provide a brief overview of current scientific literature on resveratrol, its plausible mechanism(s) of action, its potential use and current limitations as a nutritional therapeutic intervention in the eye and its related disorders.
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Affiliation(s)
- Khaled K Abu-Amero
- Department of Ophthalmology, University of Florida College of Medicine, FL 32209, USA.
- Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11424, Saudi Arabia.
| | - Altaf A Kondkar
- Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11424, Saudi Arabia.
| | - Kakarla V Chalam
- Department of Ophthalmology, University of Florida College of Medicine, FL 32209, USA.
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Bedada SK, Neerati P. Resveratrol Pretreatment Affects CYP2E1 Activity of Chlorzoxazone in Healthy Human Volunteers. Phytother Res 2015; 30:463-8. [PMID: 26680654 DOI: 10.1002/ptr.5549] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 10/13/2015] [Accepted: 11/24/2015] [Indexed: 12/15/2022]
Abstract
The purpose of the present study was to investigate the effect of resveratrol (RSV) pretreatment on CYP2E1 enzyme activity and pharmacokinetics of chlorzoxazone (CHZ) in healthy human volunteers. The open-label, two period, sequential study was conducted in 12 healthy human volunteers. A single dose of RSV 500 mg was administered once daily for 10 days during treatment phase. A single dose of CHZ 250 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after CHZ dosing at predetermined time intervals and analyzed by HPLC. RSV pretreatment significantly enhanced the maximum plasma concentration (Cmax), area under the curve (AUC) and half life (T1/2) and significantly decreased elimination rate constant (Kel), apparent oral clearance (CL/F) and apparent volume of distribution (Vd/F) of CHZ as compared to that of control. In addition, RSV pretreatment significantly decreased the metabolite to parent (6-OHCHZ/CHZ) ratios of Cmax, AUC and T1/2 and significantly increased the Kel ratio of 6-OHCHZ/CHZ, which indicated the reduced formation of CHZ to 6-OHCHZ. The results suggest that the altered CYP2E1 enzyme activity and pharmacokinetics of CHZ might be attributed to RSV mediated inhibition of CYP2E1 enzyme. Thus, there is a potential pharmacokinetic interaction between RSV and CHZ. The inhibition of CYP2E1 by RSV may provide a novel approach for minimizing the hepatotoxicity of ethanol.
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Affiliation(s)
- Satish Kumar Bedada
- Drug Metabolism and Clinical Pharmacokinetics Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, 506009, Telangana State, India
| | - Prasad Neerati
- Drug Metabolism and Clinical Pharmacokinetics Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, 506009, Telangana State, India
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Resveratrol as a Bioenhancer to Improve Anti-Inflammatory Activities of Apigenin. Nutrients 2015; 7:9650-61. [PMID: 26610561 PMCID: PMC4663613 DOI: 10.3390/nu7115485] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 11/09/2015] [Indexed: 11/30/2022] Open
Abstract
The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-1β, IL-6 and TNF-α. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%). Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin. When the action of resveratrol on the main apigenin metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a Ki value of 7.782 μM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin’s anti-inflammatory activities in the body.
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Basheer L, Schultz K, Fichman M, Kerem Z. Use of In Vitro and Predictive In Silico Models to Study the Inhibition of Cytochrome P4503A by Stilbenes. PLoS One 2015; 10:e0141061. [PMID: 26485399 PMCID: PMC4618141 DOI: 10.1371/journal.pone.0141061] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 10/01/2015] [Indexed: 01/01/2023] Open
Abstract
CYP3A4 is recognized as the main enzyme involved in the metabolism of drugs and xenobiotics in the human body and its inhibition may lead to undesirable consequences. Stilbenes, including resveratrol, belong to a group of dietary health-promoting compounds that also act as inhibitors of CYP3A4. The aim of this study was to examine the use of computer modeling of enzyme-ligand interactions to analyze and predict the inhibition of structurally related compounds. To this end, an aldehyde group was attached to resveratrol and the interactions of CYP3A4 with resveratrol, its aldehyde analogue (RA) and a known synthetic inhibitor were studied and compared in two biological models. Specifically, the metabolism of testosterone was examined in a human intestine cell line (Caco-2/TC7) and in rat liver microsomes (RLM). The results demonstrated a weak inhibitory effect of RA on CYP3A4, as compared to resveratrol itself, in both biological models. Human CYP3A4 was more susceptible to inhibition than the commonly used model isozyme from rat. Modeling of the binding site of CYP3A4 revealed a combination of three types of interactions: hydrophobic interactions, electrostatic interactions and hydrogen bonds. A docking simulation revealed that the RA lacked an important binding feature, as compared to resveratrol, and that that difference may be responsible for its lower level of affinity for CYP3A4. Software analysis of binding affinity may serve as a predictive tool for designing new therapeutic compounds in terms of inhibition of CYP3A4 and help to reveal the biochemical nature of the interactions of dietary compounds, herbal compounds and drugs whose metabolism is mediated by this enzyme.
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Affiliation(s)
- Loai Basheer
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Keren Schultz
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Merav Fichman
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Zohar Kerem
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
- * E-mail:
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Casas-Grajales S, Muriel P. Antioxidants in liver health. World J Gastrointest Pharmacol Ther 2015; 6:59-72. [PMID: 26261734 PMCID: PMC4526841 DOI: 10.4292/wjgpt.v6.i3.59] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 06/04/2015] [Accepted: 06/18/2015] [Indexed: 02/06/2023] Open
Abstract
Liver diseases are a worldwide medical problem because the liver is the principal detoxifying organ and maintains metabolic homeostasis. The liver metabolizes various compounds that produce free radicals (FR). However, antioxidants scavenge FR and maintain the oxidative/antioxidative balance in the liver. When the liver oxidative/antioxidative balance is disrupted, the state is termed oxidative stress. Oxidative stress leads to deleterious processes in the liver and produces liver diseases. Therefore, restoring antioxidants is essential to maintain homeostasis. One method of restoring antioxidants is to consume natural compounds with antioxidant capacity. The objective of this review is to provide information pertaining to various antioxidants found in food that have demonstrated utility in improving liver diseases.
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Katen AL, Roman SD. The genetic consequences of paternal acrylamide exposure and potential for amelioration. Mutat Res 2015; 777:91-100. [PMID: 25989052 DOI: 10.1016/j.mrfmmm.2015.04.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Revised: 03/31/2015] [Accepted: 04/08/2015] [Indexed: 06/04/2023]
Abstract
Acrylamide is a toxin that humans are readily exposed to due to its formation in many carbohydrate rich foods cooked at high temperatures. Acrylamide is carcinogenic, neurotoxic and causes reproductive toxicity when high levels of exposure are reached in mice and rats. Acrylamide induced effects on fertility occur predominantly in males. Acrylamide exerts its reproductive toxicity via its metabolite glycidamide, a product which is only formed via the cytochrome P450 detoxifying enzyme CYP2E1. Glycidamide is highly reactive and forms adducts with DNA. Chronic low dose acrylamide exposure in mice relevant to human exposure levels results in significantly increased levels of DNA damage in terms of glycidamide adducts in spermatocytes, the specific germ cell stage where Cyp2e1 is expressed. Since cells in the later stages of spermatogenesis are unable to undergo DNA repair, and this level of acrylamide exposure causes no reduction in fertility, there is potential for this damage to persist until sperm maturation and fertilisation. Cyp2e1 is also present within epididymal cells, allowing for transiting spermatozoa to be exposed to glycidamide. This could have consequences for future generations in terms of predisposition to diseases such as cancer, with growing indications that paternal DNA damage can be propagated across multiple generations. Since glycidamide is the major contributor to DNA damage, a mechanism for preventing these effects is inhibiting the function of Cyp2e1. Resveratrol is an example of an inhibitor of Cyp2e1 which has shown success in reducing damage caused by acrylamide treatment in mice.
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Affiliation(s)
- Aimee L Katen
- Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales 2308, Australia
| | - Shaun D Roman
- Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales 2308, Australia; The Australian Research Council Centre of Excellence in Biotechnology and Development, Callaghan, New South Wales 2308, Australia; The Priority Research Centres for Reproductive Sciences and Chemical Biology, University of Newcastle, Callaghan, New South Wales 2308, Australia.
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