Cardiac hypertrophy is a risk factor for heart failure and is usually less common in young women than in men. Cytochrome P450 (CYP) enzymes in the heart metabolize arachidonic acid into hydroxyeicosatetraenoic acids (HETEs), which generally have hypertrophic effects, and epoxyeicosatrienoic acids, which have cardioprotective effects. In this study, we aimed to investigate sex-specific differences in cardiac hypertrophy and cardiac CYP, HETE, and epoxyeicosatrienoic acid levels in response to pressure overload. Adult male and female Sprague-Dawley rats were subject to sham or abdominal aortic constriction (AAC) surgeries. Five weeks postsurgery, cardiac function was assessed by echocardiography. The mRNA and protein levels of hypertrophic markers and CYP enzymes were measured by real-time polymerase chain reaction and Western blot. Heart tissue HETE levels and microsomal formation of HETEs and epoxyeicosatrienoic acids were measured by liquid chromatography-tandem mass spectrometry. Our results show significant sex-specific differences in AAC-induced cardiac hypertrophy. Echocardiography and ventricular wall measurements showed more hypertrophy in male rats. Some hypertrophic markers were significantly upregulated only in male AAC rats and were significantly higher in the hearts of male rats compared to female AAC rats. Different CYP hydroxylases such as CYP1B1, CYP4A, and CYP4F and epoxygenases such as CYP2C and CYP2J10 were significantly upregulated in the hearts of male AAC rats only. The heart level of 12(R)-HETE and the microsomal formation of several HETEs were also significantly increased only in male rats. In conclusion, male rats developed stronger AAC-induced cardiac hypertrophy compared to female rats, which was accompanied by a significant increase in cardiac CYP enzymes and HETEs. SIGNIFICANCE STATEMENT: Previous studies demonstrated that male rats experience more severe cardiac hypertrophy compared to female rats. To our knowledge, this research is the first to investigate and compare the expression of cytochrome P450 enzymes and arachidonic acid metabolites in male and female rat hearts following pressure overload-induced hypertrophy. This study highlights significant sex-specific differences in cytochrome P450-mediated metabolism during hypertrophy, providing valuable insights into the molecular mechanisms underlying these responses and identifying potential targets for sex-specific therapies in cardiac diseases.

Arsenic, as a metalloid, has the ability to move and transform in different environmental media. Its widespread contamination has become a significant environmental problem and public concern. Arsenic can jeopardize multiple organs through various pathways, influenced by environmental bioprocesses. This article provides a comprehensive overview of current research on the cardiovascular hazards of arsenic. A bibliometric analysis revealed that there are 376 papers published in 145 journals, involving 40 countries, 631 institutions, and 2093 authors, all focused on arsenic-related concerns regarding cardiovascular health. China and the U.S. have emerged as the central hubs of collaborative relationships and have the highest number of publications. Hypertension and atherosclerosis are the most extensively studied topics, with redox imbalance, apoptosis, and methylation being the primary mechanistic clues. Cardiovascular damage caused by arsenic includes arrhythmia, cardiac remodeling, vascular leakage, and abnormal angiogenesis. However, the current understanding is still inadequate over cardiovascular impairments, underlying mechanisms, and precautionary methods of arsenic, thus calling an urgent need for further studies to bridge the gap between environmental processes and arsenic hazards.

Arsenic is a hazardous heavy metalloid that imposes threats to human health globally. It is widely spread throughout the environment in various forms. Arsenic-based compounds are either inorganic compounds (iAs) or organoarsenicals (oAs), where the latter are biotically generated from the former. Exposure to arsenic-based compounds results in varying biochemical derangements in living systems, leading eventually to toxic consequences. One important target for arsenic in biosystems is the network of metabolic enzymes, especially the superfamily of cytochrome P450 enzymes (CYPs) because of their prominent role in both endobiotic and xenobiotic metabolism. Therefore, the alteration of the CYPs by different arsenicals has been actively studied in the last few decades. We have previously summarized the findings of former studies investigating arsenic associated modulation of different CYPs in human experimental models. In this review, we focus on non-human models to get a complete picture about possible CYPs alterations in response to arsenic exposure.

Cytochrome P450 (P450) enzymes are monooxygenases that are expressed hepatically and extrahepatically and play an essential role in xenobiotic metabolism. Substantial scientific evidence indicates sex-specific differences between males and females in disease patterns and drug responses, which could be attributed, even partly, to differences in the expression and/or activity levels of P450 enzymes in different organs. In this study, we compared the mRNA and protein expression of P450 enzymes in different organs of male and female Sprague-Dawley rats by real-time polymerase chain reaction and western blot techniques. We found significant sex- and organ-specific differences in several enzymes. Hepatic Cyp2c11, Cyp2c13, and Cyp4a2 showed male-specific expression, whereas Cyp2c12 showed female-specific expression. Cyp2e1 and Cyp4f enzymes demonstrated higher expression in the female heart and kidneys compared with males; however, they showed no significant sexual dimorphism in the liver. Male rats showed higher hepatic and renal Cyp1b1 levels. All assessed enzymes were found in the liver, but some were not expressed in other organs. At the protein expression level, CYP1A2, CYP3A, and CYP4A1 demonstrated higher expression levels in the females in several organs, including the liver. Elucidating sex-specific differences in P450 enzyme levels could help better understand differences in disease pathogeneses and drug responses between males and females and thus improve treatment strategies. SIGNIFICANCE STATEMENT: This study characterized the differences in the mRNA and protein expression levels of different cytochrome P450 (P450) enzymes between male and female rats in the heart, liver, lung, kidney, brain, and small intestine. It demonstrated unique sex-specific differences in the different organs. This study is considered a big step towards elucidating sex-specific differences in P450 enzyme levels, which is largely important for achieving a better understanding of the differences between males and females in the disease's processes and treatment outcomes.

Arsenic is well-recognized as one of the most hazardous elements which is characterized by its omnipresence throughout the environment in various chemical forms. From the simple inorganic arsenite (iAsIII) and arsenate (iAsV) molecules, a multitude of more complex organic species are biologically produced through a process of metabolic transformation with biomethylation being the core of this process. Because of their differential toxicity, speciation of arsenic-based compounds is necessary for assessing health risks posed by exposure to individual species or co-exposure to several species. In this regard, exposure assessment is another pivotal factor that includes identification of the potential sources as well as routes of exposure. Identification of arsenic impact on different physiological organ systems, through understanding its behavior in the human body that leads to homeostatic derangements, is the key for developing strategies to mitigate its toxicity. Metabolic machinery is one of the sophisticated body systems targeted by arsenic. The prominent role of cytochrome P450 enzymes (CYPs) in the metabolism of both endobiotics and xenobiotics necessitates paying a great deal of attention to the possible effects of arsenic compounds on this superfamily of enzymes. Here we highlight the toxicologically relevant arsenic species with a detailed description of the different environmental sources as well as the possible routes of human exposure to these species. We also summarize the reported findings of experimental investigations evaluating the influence of various arsenicals on different members of CYP superfamily using human-based models.

Glutathione S-transferases (GSTs) are a key enzyme superfamily involved in the detoxification and cytoprotection of a wide variety of xenobiotics, such as carcinogens, anticancer drugs, environmental toxicants, and endogenously produced free radicals. In the liver, the hGSTA1 isoenzyme is the most abundant and catalyzes the glutathione conjugation of a wide range of electrophiles and has been the principal GST responsible for xenobiotic detoxification. Given the critical role of this enzyme in several cellular processes, particularly cell detoxification, understanding the molecular mechanisms underlying the regulation of hGSTA1 expression is critical. Therefore, the aim of the present study was to investigate whether AHR is involved in the modulation of hGSTA1 gene expression and to characterize the molecular mechanism through which AHR exerts this regulation. Two xenobiotic response elements (XREs) were located at -602 bp and -1030 bp from the transcription start site at the hGSTA1 gene promoter. After treatment of HepG2 cells with beta-naphthoflavone (β-NF), an AHR agonist, induction of hGSTA1 mRNA was observed. This effect was mediated by the recruitment of AHR to the hGSTA1 gene promoter and its transactivation, as indicated by the ChIP, EMSA and luciferase activity assays. The increase in hGSTA1 transcription regulated by AHR also resulted in enhanced levels of hGSTA1 protein and activity. Taken together, our data suggest that AHR ligands have the potential to modify xenobiotic and endobiotic metabolism mediated by hGSTA1, thereby altering the detoxification of xenobiotics, steroidogenesis and the efficacy of chemotherapeutic agents.

In the present study, time-dependency of the induction effect of a selective inducer on the activity, protein and mRNA levels of cytochromes P450 1A1/2 (CYP1A1/2), NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferases (GSTA), in primary culture of rat hepatocytes was tested and evaluated. To show the differences in responses of tested enzymes, the common aryl hydrocarbon receptor (AhR) ligand agonist, beta-naphthoflavone (BNF), was used. Induction of CYP1A1/2 by BNF was detected at all time intervals and at all levels (i.e., mRNA, protein, enzyme activity). Different responses of NQO1 and GSTA upon BNF treatment were observed. Our results demonstrate that the responses of different xenobiotic-metabolizing enzymes to the inducer vary in time and depend on the measured parameter. For these reasons, an induction study featuring only one-time interval treatment and/ or one parameter testing could produce misleading information.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant and its toxicity is mediated by the aryl hydrocarbon receptor (AHR). Mechanisms of TCDD cardiovascular toxicity consist of oxidative stress, growth factor modulation, and ionic current alteration. It is indicated that the rodent cardiovascular system is a target for TCDD cardiomyopathy. Here, our understanding of TCDD cardiovascular toxicity is reviewed.