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Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases
Li-Qun Yang, Shen-Jing Li, Yun-Fei Cao, Xiao-Bo Man, Wei-Feng Yu, Hong-Yang Wang, Meng-Chao Wu
Li-Qun Yang, Yun-Fei Cao,
Wei-Feng Yu, Department of
Anesthesiology, Eastern Hepatobiliary Surgery Hospital, the Second Military
Medical University, Shanghai 200438, China
Shen-Jing Li, Xiao-Bo Man, Hong-Yang
Wang, International Cooperation
Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the
Second Military Medical University, Shanghai 200438, China
Meng-Chao Wu, Department
of Clinical Surgery, Eastern Hepatobiliary Surgery Hospital, the Second Military
Medical University, Shanghai 200438, China
Surported by Military
Medical Science Found of China, No.98Q050
Correspondence to: Dr.
Wei-Feng Yu, Department of Anesthesiology, Eastern Hepatobiliary Surgery
Hospital, the Second Military Medical University, Shanghai 200438, China. liqunyang@yahoo.com
Telephone: +86-21-25070783
Fax: +86-21-25070783
Received:
2002-09-13 Accepted: 2002-10-18
Abstract
AIM: To determine whether parenchymal
cells or hepatic cytochrome P450 protein was changed in chronic liver diseases,
and to compare the difference of CYP3A4 enzyme and its gene expression between
patients with hepatic cirrhosis and obstructive jaundice, and to investigate the
pharmacologic significance behind this difference.
METHODS: Liver samples were obtained
from patients undergoing hepatic surgery with hepatic cirrhosis (n=6) and
obstructive jaundice (n=6) and hepatic angeioma (controls,n=6).
CYP3A4 activity and protein were determined by Nash and western bloting using
specific polychonal antibody, respectively.Total hepatic RNA was extracted and
CYP3A4cDNA probe was prepared according the method of random primer marking, and
difference of cyp3a4 expression was compared among those patients by Northern
blotting.
RESULTS: Compared to control group, the
CYP3A4 activity and protein in liver tissue among patients with cirrhosis were
evidently reduced. (P<0.01) Northern blot showed the same change in
its mRNA levels. In contrast, the isoenzyme and its gene expression were not
changed among patients with obstructive jaundice.
CONCLUSION: Hepatic levels of P450s and
its CYP3A4 isoform activity were selectively changed in different chronic liver
diseases. CYP3A4 isoenzyme and its activity declined among patients with hepatic
cirrhosis as expression of cyp3a4 gene was significantly reduced. Liver's
ability to eliminate many clinical
therateutic drug substrates would decline consequently, These findings may have
practical implications for the use of drugs in patients with cirrhosis and
emphasize the need to understand the metabolic fate of therapeutic compounds.
Elucidation of the reasons for these different changes in hepatic CYP3A4 may
provide insight into more fundamental aspects and mechanisms of imparied liver
function.
Yang LQ, Li SJ, Cao YF, Man XB, Yu WF, Wang HY, Wu MC. Different alterations of
cytochrome P450 3A4 isoform and its gene expression in livers of patients with
chronic liver diseases. World J Gastroenterol 2003; 9(2): 359-363
http://www.wjgnet.com/1007-9327/9/359.htm
INTRODUCTION
Hepatic cytochrome P450 enzymes
constitute a superfamily of hemoproteins which play a major role in the
metabolism of endogenous compounds and in the detoxification of xenobiotic
molecules, includeing anesthetics and carcinogens[1-3]. About 200
CYPs have been found in the past 20 years, and many factors including age,
gender, nutrition, hormone and general or local pathol ogic reaction affect CYPs,
and the biotransformation of many clinical therapeutic drugs would be changed.
P450 3A4 is one of the most important forms in human, mediating the metabolism
of about 70 % of therapeutic drugs and endogenous compounds[4-6].
Although the mechanism and consequences of
regulation of P450s by drugs and chemicals have been intensively studied, the
mechanisms by which P450s are changed by hepatic pathological factors still
remained unclear[7-11]. Hepatic cirrhosis and obstructive jaundice
are most common chronic hepatobiliary diseases among Chinese people, the change
of CYPs with cirrhosis and jaundice provided us fundamental knowledge about the
effect of pathological factors on P450s[12-15]. The aim of this study
is to determine the alterations of CYP3A4 enzyme and its gene expression in
patients with those chronic liver diseases, and to investigate the pharmacologic
and clinical significance behind this alterations.
MATERIALS AND METHODS
Materials
pBS
M13 CYP3A4 plasmid was kindly provided by Prof Ying-Nian Yu (Zhe-jiang
University, China). Rabbit anti-human CYP3A4 polyclonal antibody was
purchased from Chemicon (San Diego, CA); HRP taged sheep
anti-rabbit antibody was purchased from PharMingen (Mannheim, Germany);
glucose 6- phosphoric acid, erythromycin, Lowry's phenol
reagent, glucose 6-phosphoric transferase, acetic ammonium, acetyl-acetone, and
NADP were purchased from Sigma Chemical (St. Louis, MO); and all
other reagents used in this study were of analytical grade.
Source of human liver tissues and patient characters
Human liver samples (30-50 g)
were taken from patients undergoing hepatic surgery. Patients had not receive
medication of CYPs activator and inhibitor (rifampicin, dexamethasone, propofol,
etc) before the surgery. None of the patients were habitual consumers of alcohol
or other drugs. A total of 18 liver samples from 15 men and 3 women were used.
They were all cases admitted from 2000 to 2001 in Eastern Hepatobiliary Surgery
Hospital in Shanghai, China. Informed content was obtained from all patients for
subsequent use of their specimen tissues. These specimens were immediately
dissected into small pieces under aseptic condition within half an hour, quickly
frozen and preserved in liquid nitrogen before subsequent procedure.
Patients?characters and liver function are shown in Table 1.
Table 1 Clinicopathological
characteristics of patients studied and their Pugh class
| Groups | Median Age (yrs) | Gender F/M | Smoking (n) | Ethanol (n) | Pugh Class A,B,C |
| C (n=6) | 42(21-56) | 2/4 | 2 | 1 | A(6) |
| H (n=6) | 38(28-61) | 1/5 | 1 | 1 | A(4),B(2) |
| O (n=6) | 44(27-65) | 0/6 | 1 | 2 | B(6) |
C: controls; H: hepatic
cirrhosis; O: obstructive jaundice.
Preparation of microsomes
Liver tissues were subsequently
homogenized in ice-cold 0.1 mol/L Tris-HCl buffer containing 1.15 % KCl(pH7.4)
and to yield a liver homogenate tissue concentration of 0.33 g/ml. Microsomal
fractions were prepared by differential ultracentrifugation. After tissue
homogenization in 20 mM Tris-HCl buffer, pH 7.4, containing 0.15 M KCl, the
microsomal fraction was isolated from the supernatant of a 20-min 9 000×g spin
by ultracentrifugation. The microsomal precipitate was suspended in 100 mM
potassium phosphate buffer, pH 7.4, and recentrifuged at 105 000×g for
an additional 60 min. The final precipitate was suspended in 10 Mm Tris-HCl
buffer (pH 7.4) containing 10 mM EDTA and 20 %(v/v) glycerol. Liver microsomal
protein contents were determined following the methods of Lowry et al[16],
using bovine serum albumin as standard.
Microsomes P450s and CYP3A4 activity assays
CO-bound total cytochrome P450
content was determined by the method of Omura et al[17].
Spectra were recorded using a Shimadzu UV-250 double-beam spectrophotometer.
CYP3A4 specific activity was determined by N-demethylation of erythromycin using
the Nash method as previously described[18].
Immunoquantition of CYP3A4 isoform protein by western blot analysis
Hepatic microsomal proteins
were resolved by SDS-PAGE with vertical mini-gel electrophoresis equipment.
Samples of liver microsomal protein (10 mg/lane)
were denatured in 10 ml
loading buffer (4 ml distilled water, 1 ml 0.5M Tris-HCl, pH
6.8, 0.8 ml glycerol, 1.6 ml 10 % w/v SDS, 0.4 ml mercaptoethanol, 0.05 ml 0.05
% w/v Pyronin Y) and were separated on a 10 % w/v resolving gel. Proteins were
transferred from the polyacrylamide gel to the nitrocellulose sheets by an
electrophoretic method, and probed with rabbit anti-human CYP3A4 polyclonal
antibody (not cross-reactive with other rat P450s) according to supplied
protocol. CYP3A4 protein was detected by secondary conjugation to the primary
antibody by a HRP-linked sheep anti-rabbit second antibody using
diaminobenzidine as substrate.
Northern blot analysis CYP3A4 mRNA
Total RNA was isolated from frozen
human liver tissues by the acid guanidinium thiocyanate-phenol-chloroform one
step extraction method as previously described[19], 20 mg of RNA was
size-fractionated on a 1.0 % agarose gel containing 2.2 mol/L formaldehyde, and
then transferred into nitrocellulose membrane (BA85, Schleicher
Schuell, Germany). The membrane wes dried in a vacuum drying over at
80 ℃ for 2 h and sealed in a plastic bag for use. CYP3A4 probe wes cut from pBS
M13 CYP3A4 plasmid by Hand III. Hybridization was performed in the presence of
the appropriate 32P-labeled probes. The membrane was washed twice at
room temperture in 2×SSC, 0.1 % SDS for 30 min, once at 65
℃ in 1×SSC, 0.1 % SDS for 30 min and once at 65
℃ in 0.1×SSC,
0.1 % SDS for 30 min. Membranes was then exposed to X-ray films(Fujifilms,
Tokyo, Japan) at -70 ℃ for a week and analyzed by Phosphor Image (FLA
2000, Fujifilm, Japan). The difference of CYP3A4mRNA was compared among three
groups.
Statistical analysis
Data was analyzed using the c2
test. A P<0.05 was considerd significant.
RESULTS
P450 and CYP3A4 activity changes in
chronic liver diseases
As shown in Table 2, compared
with controls, the hepatic microsome protein and total P450 content remained
unchange in the patients with hepatic cirrhosis and obstructive jaundice, but
CYP3A4 activity in the liver tissue of patients with cirrhosis liver was
evidently reduced. This change was not seen in the obstructive jaundice group.
Table 2 Microsomal protein, total P450
content and CYP3A4 content and its activity among three groups (x±s)
| C | H | O | |
| Microsome protein (g/L) | 10.32±3.98 | 9.57±3.72 | 9.42±3.26 |
| P450 content (nmol/mg protein) | 0.99±0.16 | 0.94±0.151 | 0.89±0.18 |
| CYP3A4 activity (nmol/min/mg protien) | 3.01±0.74 | 1.78±0.653a | 2.89±0.65 |
aP<0.01 vs
controls C: controls; H: hepatic cirrhosis; O: obstructive jaundice.
Change of CYP3A4 isoform protein
Hepatic CYP3A4 protein expression
was shown in Figure 1 by western blot analysis. CYP3A4 protein in liver tissues
was also reduced in the patients with cirrhosis liver, but in obstructive
jaundice, there was no change of as compared with controls.
Figure 1
Western Blot analysis of CYP3A4 isoform protein among three groups, compared
with controls (tagged by "C1-6". CYP3A4 protein content in
liver tissues among patients with cirrhosis (tagged by "H1-6"
reduced. but in obstructive jaundice (tagged by "O1-6",
There was no change of CYP3A4 protein expression.
Change of CYP3A4mRNA in chronic liver diseases
As shown in Figure 2, CYP3A4 probe
was cut from pBS M13 CYP3A4 plasmid by Hand III, we got a 800 bp cDNA
fragment as expected.
Northern blot analysis showed that CYP3A4 was
expressed well in human liver tissues, which agreed with other reports[20-23].
In patients with cirrhosis (shown in Figure 3), CYP3A4mRNA reduced significantly
as compared with controls, but no change happened in the jaundice group.
Figure 2
The results of substratum electrophoresis in pBS M13 CYP3A4 plasmid. Lane 1: pBS
M13 CYP3A4 (Hind III), Lane 2: Marker (1kb DNA ladder).
Figure 3 Northern
blot analysis mRNA expression of CYP3A4 isoform in liver tissues among three
groups. Total RNA was isolated without degradation and each bottom panel showed
an equal amount of total RNA loading as indicated in 28 s and 18 s rRNA.
CYP3A4mRNA was expressed well in human liver tissues, of patients with
cirrhosis(tagged by "H", CYP3 A4mRNA was reduced significantly
compared with control(tagged by "C",
but no decline happened in jaundice group(tagged by "O".
DISCUSSION
CYP3A appears to be one of the most
important human enzymes as approximately 60 % of oxidised drugs are
biotransformed. The isoforms of CYP3A in humans include 3A3, 3A4, 3A5 and 3A7,
each of these enzymes shared at least 85 % amino acid sequence homology[24].
CYP3A4 is the predominant isoform of CYP3A in adult humans. It can catalyse a
remarkable number of metabolic processes including aliphatic oxidation, aromatic
hydroxylation, N-dealkylation, O-demethylation, S-demethylation, oxidative
deamination, sulfoxide formation, N-oxidation and N-hydroxylation. This usually
produced inactivation and elimination of most pharmaceuticals. A number of drugs
from a broad range of therapeutic categories are CYP3A4 substrates. The change
of CYP3A4 isform was the main reason for enhancement or reduction of drug
elimination[25-27].
In our studies, total P450 contents of 18 Chinese
patients were obviously lower than results those reported about Caucasian. (1
pmol/mg vs 5-6 pmol/mg), and the activity of CYP3A4 isoform was also
lower[28-30]. Although CYP3A4 drug metabolizing activity varied
widely among individuals, it had a unimodal population distribution and did not
appear to be subject to genetic polymorphism as seen with other CYP isoforms
(2D6, 2C9 and 2C19)[31-34]. The wide inter races variability was
likely, in part, to be caused by ethnic or cultural differences, which might be
related to an interaction between habit and diet. Therefore we could not draw
any conclusion about the normal distribution character of CYPs in Chinese
because of the limited sample number and experimental conditions. More detailed
and complete studies should be performed for analysising the distribution of
CYPs in Chinese in the near future[35].
Most information on drug metabolism impairment at
pathologic status has been obtained in rodent in vivo or in vitro
models, and most of these studies have focused on the effects of IFNs and the
major inflammatory cytokines, namely, IL-6, IL1 and TNFa[36-39], but
relatively few studies have examined the effect of liver disease on human CYP
expression. Hepatic cirrhosis and obstructive jaundice are most common chronic
hepatobiliary disease in Chinese, the change of CYPs with cirrhosis and jaundice
can provide us basic knowledge about the effect of pathological factors on
P450s. The present study demonstrated that, in patients with cirrhosis,
CYP3A4-mediated erythromycin N-demethylation activity and 3A4 protein were
significantly less than in controls, but the total P450 content and hepatic
microsome protein still remained unchanged. These results suggest that family
ingredients of P450s have changed in the cirrhosis. That is, CYP family 1, 2 may
enhance following with CYP3A reduced, since CYP1 and CYP2 families play a major
role in biotransformation of most carcinogens, but few studies described whether
high morbidity of hepatic cancer in cirrhosis is correlated with these changes
of drug metabolic enzymes[40].
Although many factors including age, gender,
nutrition, hormone and general or local pathologic reaction affect drug
elimination, the enzymatic activity as well as content of P450s is still a basic
reason for change of drug metabolism, and the biotransformation of many clinical
therapeutic drugs either enhanced or reduced[41-43]. This study is
for the first time to examine simultaneously in patients with liver diseases the
hepatic P450 protein level, isoform activity as well as its mRNA expression.
Significant correlations with CYP3A4 protein level, isoform activity and mRNA
expression were observed, suggesting that with the decrease of CYP3A4 mRNA
expression, RNA encoded CYP3A4 isoform protein reduced, which would cause the
decrease of CYP3A4-mediated erythromycin N-demethylation activity. Since CYP3A4
is the predominant isoform of CYP3A in adult humans, the Change of hepatic
CYP3A4 activity will change the metabolism of most clinical therapeutic drugs.
Firstly, a large number of intravenous anesthetic and sedative agents (including
diazepam, midozolam, fentanyl, lidocaine, etc.) are substrates of CYP3A4 isoform,
N-hydroxylation and N-dealkylation reactions of anesthetics reduced in cirrhosis
patiens will cause drug raccumulation, oversedative and postoperative awake
delay[44,45]. Secondly, Amiodarone, quinidine, nifedipine, berhomine
and Cyclosporin were also eliminated through CYP3A4, thus competitive inhibition
should be noticed and avoided especially when more than one drugs must be
administrated in patients with cirrhosis. These findings are in agreement with
pharmacokinetics studies that have shown reduced clearance of midozolam when
combined with fentanyl in cirrhosis, but over-dosage condition of anti-irrhythmia
drugs had more clinical signifiance than that of other therapeutic drugs[46,47].
Thirdly, as CYP3A4 also plays an important role in the biotransformation and
detoxification of many endogenetic substrates, reduction of CYP3A4 activity may
result in inactivation disorder of endogenetic substance including cholesterol,
bile acid and sex steroids, thus causing more extensive physiopathologic changes
in patients with cirrhosis, these changes, on contrary, will affect the drug
metabolic enzymes[48,49].
In summary, the present study demonstrated that,
hepatic levels of individual P450s and its CYP3A4 isoform activity can
selectively change in different chronic liver diseases. The hepatic microsome
proteins and total P450 content remained unchanged in patients with hepatic
cirrhosis and obstructive jaundice , but CYP3A4 activity and its protein level
in liver tissue among patients with cirrhosis were evidently lowered. This
change was not seen in obstructive jaundice group, and the cause of this change
may be the lowered expression of CYP3A4 mRNA. These findings may have practical
implications for the use of drugs in patients with liver diseases and emphasize
the need to understand the metabolic fate of therapeutic compounds[50,51].
Elucidation of the reasons for these different changes in hepatic P450s may
provide insight into more fundamental aspects and mechanisms of impaired liver
function in patients with chronical liver diseases.
REFERENCES
1
Kostrubsky VE,
Ramachandran V, Venkataramanan R, Dorko K, Esplen JE, Zhang S, Sinclair JF,
Wrighton SA, Strom SC.
The use of human hepatocyte cultures to study the
induction of cytochrome P-450. Drug Metab Dispos 1999; 27: 887-894
2 Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R,
Fujii-Kuriyama Y, Gonzalez FJ, Guengerich FP, Gunsalus IC,
Johnson EF. The P450 superfamily: update on new
sequences, gene mapping, and recommended nomenclature.
DNA Cell Biol 1991; 10: 1-10
3 Capdevila JH, Harris RC, Falck JR. Microsomal cytochrome
P450 and eicosanoid metabolism.
Cell Mol Life Sci 2002; 59: 780-789
4 Guengerich FP. Cytochrome P-450 3A4: regulation and role in
drug metabolism. Annu Rev Pharmacol Toxicol 1999; 39: 1-17
5 Raucy JL, Allen SW. Recent advances in P450 research.
Pharmacogenomics J 2001; 1: 178-186
6 Zhu-Ge J, Yu YN, Qian YL, Li X. Establishment of a
transgenic cell line stably expressing human cytochrome P450 2C18 and
identification of a CYP2C18 clone with exon 5 missing.
World J Gastroenterol 2002; 8: 888-892
7 Goodwin B, Redinbo MR, Kliewer SA. Regulation of cyp3a gene
transcription by the pregnane x receptor.
Annu Rev Pharmacol Toxicol 2002; 42: 1-23
8 Quattrochi LC, Guzelian PS. Cyp3A regulation: from
pharmacology to nuclear receptors. Drug Metab Dispos 2001; 29: 615-622
9 Waxman DJ. P450 gene induction by structurally diverse
xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR.
Arch Biochem Biophys 1999; 369: 11-23
10 Nicholson TE, Renton KW. Modulation of cytochrome P450 by inflammation
in astrocytes. Brain Res 1999; 827: 12-18
11 Dogra SC, Whitelaw ML, May BK. Transcriptional activation of
cytochrome P450 genes by different classes of chemical inducers.
Clin Exp Pharmacol Physiol 1998; 25: 1-9
12 Lieber CS. Ethanol metabolism, cirrhosis and alcoholism. Clin Chim
Acta 1997; 257: 59-84
13 Paintaud G, Bechtel Y, Brientini MP, Miguet JP, Bechtel PR. Effects of
liver diseases on drug metabolism.
Therapie 1996; 51: 384-389
14 Brockmoller J, Roots I. Assessment of liver metabolic function.
Clinical implications. Clin Pharmacokinet 1994; 27: 216-248
15 Murray M. P450 enzymes. Inhibition mechanisms, genetic regulation and
effects of liver disease.
Clin Pharmacokinet 1992; 23: 132-146
16 Lowry OH, Passonneau JV. Some recent refinements of quantitative
histochemical analysis. Curr Probl Clin Biochem
1971; 3: 63-84
17 Omura T. Forty years of cytochrome P450. Biochem Biophys Res Commun
1999; 266: 690-698
18 Hover CG, Kulkarni AP. Lipoxygenase-mediated hydrogen
peroxide-dependent N-demethylation of N, N-dimethylaniline and
related compounds. Chem Biol Interact 2000; 124:
191-203
19 Chomczynski P, Sacch N. Single-step method of RNA isolation by acid
guanidinium thiocyanate-phenol-chloroform extraction.
Anal Biochem 1987; 162: 156-159
20 Goodwin B, Hodgson E, D扖osta
DJ, Robertson GR, Liddle C. Transcriptional regulation of the human CYP3A4 gene
by the
constitutive
androstane receptor. Mol Pharmacol 2002; 62: 359-365
21 Lin YS, Dowling AL, Quigley SD, Farin FM, Zhang J, Lamba J, Schuetz EG,
Thummel KE. Co-regulation of CYP3A4 and
CYP3A5
and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol
2002; 62: 162-172
22 Finnstrom N, Thorn M, Loof L, Rane A. Independent patterns of
cytochrome P450 gene expression in liver and blood in
patients
with suspected liver disease. Eur J Clin Pharmacol 2001; 57: 403-409
23 Rodriguez-Antona C, Donato MT, Pareja E, Gomez-Lechon MJ, Castell JV.
Cytochrome P-450 mRNA expression in human
liver
and its relationship with enzyme activity. Arch Biochem Biophys 2001; 393:
308-315
24 Mitra AK, Patel J. Strategies to overcome simultaneous P-glycoprotein
mediated efflux and CYP3A4 mediated metabolism of
drugs.
Pharmacogenomics 2001; 2: 401-415
25 de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450
3A: ontogeny and drug disposition.
Clin
Pharmacokinet 1999; 37: 485-505
26 Hakkola J, Pelkonen O, Pasanen M, Raunio H. Xenobiotic-metabolizing
cytochrome P450 enzymes in the human feto-placental
unit:
role in intrauterine toxicity. Crit Rev Toxicol 1998; 28: 35-72
27 Inaba T, Nebert DW, Burchell B, Watkins PB, Goldstein JA, Bertilsson
L, Tucker GT. Pharmacogenetics in clinical pharmacology
and
toxicology. Can J Physiol Pharmacol 1995; 73: 331-338
28 El-Sankary W, Bombail V, Gibson GG, Plant N. Glucocorticoid-Mediated
Induction of CYP3A4 is Decreased by Disruption of a
Protein:
DNA Interaction Distinct from the Pregnane X Receptor Response Element. Drug
Metab Dispos 2002; 30: 1029-1034
29 Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9
Isoforms to N-Demethylation of Ketamine in Human Liver
Microsomes.
Drug Metab Dispos 2002; 30: 853-858
30 Shu Y, Cheng ZN, Liu ZQ, Wang LS, Zhu B, Huang SL, Ou-Yang DS, Zhou HH.
Interindividual variations in levels and activities
of
cytochrome P-450 in liver microsomes of Chinese subjects. Acta Pharmacol Sin
2001; 22: 283-288
31 Tenneze L, Tarral E, Ducloux N, Funck-Brentano C. Pharmacokinetics and
electrocardiographic effects of a new
controlled-release
form of flecainide acetate: Comparison with the standard form and influence of
the CYP2D6 polymorphism.
Clin
Pharmacol Ther 2002; 72: 112-122
32 Cai L, Yu SZ, Zhang ZF. Cytochrome P450 2E1 genetic polymorphism and
gastric can c er in Changle, Fujian Province.
World
J Gastroenterol 2001; 7: 792-795
33 Zheng YX, Chan P, Pan ZF, Shi NN, Wang ZX, Pan J, Liang HM, Niu Y,
Zhou XR, He FS. Polymorphism of metabolic genes
and
susceptibility to occupational chronic manganism. Biomarkers 2002; 7:
337-346
34 Dahl ML. Cytochrome p450 phenotyping/genotyping in patients receiving
antipsychotics: useful aid to prescribing?
Clin
Pharmacokinet 2002; 41: 453-470
35 Bertilsson L. Geographical/interracial differences in polymorphic drug
oxidation. Current state of knowledge of cytochromes
P450
(CYP) 2D6 and 2C19. Clin Pharmacokinet 1995; 29: 192-209
36 Renton KW. Alteration of drug biotransformation and elimination during
infection and inflammation.
Pharmacol
Ther 2001; 92: 147-163
37 Warren GW, van Ess PJ, Watson AM, Mattson MP, Blouin RA.Cytochrome
P450 and antioxidant activity in interleukin-6
knockout
mice after induction of the acute-phase response. Interferon Cytokine Res 2001;
21: 821-826
38 De Smet K, Loyer P, Gilot D, Vercruysse A, Rogiers V, Guguen-Guillouzo
C. Effects of epidermal growth factor on CYP
inducibility
by xenobiotics, DNA replication, and caspase activations in collagen I gel
sandwich cultures of rat hepatocytes.
Biochem
Pharmacol 2001; 61: 1293-1303
39 Okamoto T, Okabe S. Minimal effect of cytokine-independent hepatitis
induced by anti-Fas antibodies on hepatic cytochrome
P450
gene expression in mice. Int J Mol Med 2000; 6: 459-462
40 Shoda T, Mitsumori K, Onodera H, Toyoda K, Uneyama C, Takada K, Hirose
M. Liver tumor-promoting effect of
beta-naphthoflavone,
a strong CYP 1A1/2 inducer, and the relationship between CYP 1A1/2 induction and
Cx32 decrease
in
its hepatocarcinogenesis in the rat. Toxicol Pathol 2000; 28: 540-547
41 Tanaka E. Gender-related differences in pharmacokinetics and their
clinical significance. J Clin Pharm Ther 1999; 24: 339-346
42 Morgan ET, Sewer MB, Iber H, Gonzalez FJ, Lee YH, Tukey RH, Okino S,
Vu T, Chen YH, Sidhu JS, Omiecinski CJ. Physiological
and
pathophysiological regulation of cytochrome P450. Drug Metab Dispos 1998; 26:
1232-1240
43 Imaoka S, Funae Y. The physiological role of P450-derived arachidonic
acid metabolites.
Nippon
Yakurigaku Zasshi 1998; 112: 23-31
44 Vuyk J. Clinical interpretation of pharmacokinetic and pharmacodynamic
propofol-opioid interactions.
Acta
Anaesthesiol Belg 2001; 52: 445-451
45 Oda Y, Mizutani K, Hase I, Nakamoto T, Hamaoka N, Asada A.Fentanyl
inhibits metabolism of midazolam: competitive
inhibition
of CYP3A4 in vitro. Br J Anaesth 1999; 82: 900-903
46 Nims RW, Prough RA, Jones CR, Stockus DL, Dragnev KH, Thomas PE, Lubet
RA. In vivo induction and in vitro inhibition of
hepatic
cytochrome P450 activity by the benzodiazepine anticonvulsants clonazepam and
diazepam. Drug Metab Dispos
1997;
25: 750-756
47 Iribarne C, Dreano Y, Bardou LG, Menez JF, Berthou F. Interaction of
methadone with substrates of human hepatic
cytochrome
P450 3A4. Toxicology 1997; 117: 13-23
48 Ourlin JC, Handschin C, Kaufmann M, Meyer UA.A. Link between
cholesterol levels and phenobarbital induction of cytochromes
P450.
Biochem Biophys Res Commun 2002; 291: 378-384
49 Staudinger J, Liu Y, Madan A, Habeebu S, Klaassen CD. Coordinate
regulation of xenobiotic and bile acid homeostasis by
pregnane
X receptor. Drug Metab Dispos 2001; 29: 1467-1472
50 Hung DY, Chang P, Cheung K, McWhinney B, Masci PP, Weiss M, Roberts
MS. Cationic drug pharmacokinetics in diseased
livers
determined by fibrosis index, hepatic protein content, microsomal activity, and
nature of drug. J Pharmacol Exp Ther
2002;
301: 1079-1087
51 Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters
JJ. Mechanisms of hepatotoxicity.
Toxicol
Sci 2002; 65: 166-176
Edited by Ma JY
