Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms (IC50 values, 3.2-33.7 muM). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF-525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds.
Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP2D6 ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System* ; Humans ; Hydrolysis ; Metabolism ; Microsomes, Liver ; Proadifen* ; Protein Isoforms

Gukang Capsules are often used in combination with drugs to treat fractures, osteoarthritis, and osteoporosis. Cytochrome P450(CYP450) mainly exists in the liver and participates in the oxidative metabolism of a variety of endogenous and exogenous substances and serves as an important cause of drug-metabolic interactions and adverse reactions. Therefore, it is of great significance to study the effect of Gukang Capsules on the activity and expression of CYP450 for increasing its clinical rational medication and improving the safety of drug combination. In this study, the Cocktail probe method was used to detect the changes in the activities of CYP1A2, CYP3A2, CYP2C11, CYP2C19, CYP2D4, and CYP2E1 in rat liver after treatment with high-, medium-and low-dose Gukang Capsules. The rat liver microsomes were extracted by the calcium chloride method, and protein expression of the above six CYP isoform enzymes was detected by Western blot. The results showed that the low-dose Gukang Capsules could induce CYP3A2 and CYP2D4 in rats, medium-dose Gukang Capsules had no effect on them, and high-dose Gukang Capsules could inhibit them in rats. The high-dose Gukang Capsules did not affect CYP2C11 in rats, but low-and medium-dose Gukang Capsules could induce CYP2C11 in rats. Gukang Capsules could inhibit CYP2C19 in rats and induce CYP1A2 in a dose-independent manner, but did not affect CYP2E1. If Gukang Capsules were co-administered with CYP1A2, CYP2C19, CYP3A2, CYP2C11, and CYP2D4 substrates, the dose should be adjusted to avoid drug interactions.
Rats ; Animals ; Cytochrome P-450 CYP1A2/metabolism* ; Cytochrome P-450 CYP2C19 ; Cytochrome P-450 CYP2E1/pharmacology* ; Rats, Sprague-Dawley ; Cytochrome P-450 Enzyme System/metabolism* ; Microsomes, Liver ; Liver ; Cytochrome P-450 CYP3A/metabolism*

Flavonoids are present in fruits, vegetables and beverages derived from plants, and in many dietary supplements or herbal remedies. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction or inhibition of these enzymes. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzyme CYP1, 2E1, 3A4 and 19. Flavonoids alter CYPs by various mechanisms, including the stimulation of gene expression via specific receptors and/or CYP protein, or mRNA stabilization and so on. But in vivo and in vitro, the effects of flavonoids are not always coincident as a result of concentrations of flavonoids, genetic and environmental factors. As well, flavonoids may interact with drugs through the induction or inhibition of their metabolism. Much attention should be paid to the metabolism interaction of the flavonoids when coadministered with other drugs.
Animals ; Aromatase ; genetics ; metabolism ; Cytochrome P-450 CYP1A1 ; antagonists & inhibitors ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 Inhibitors ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Cytochrome P-450 CYP3A Inhibitors ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Enzyme Activation ; drug effects ; Flavonoids ; pharmacology ; Humans ; RNA, Messenger ; genetics ; metabolism

The regulation mechanism of arecoline on rat hepatic CYP2E1 was studied in vivo. After oral administration of arecoline hydrobromide (AH; 4, 20 and 100 mg x kg(-1) x d(-1)) to rats for one week, the hepatic CYP2E1 mRNA level remained unchanged, but the hepatic CYP2E1 protein content was dose-dependently increased. Additionally, although the hepatic CYP2E1 activity was induced by AH treatment, the induction was attenuated with the increase in dosage. The results indicate that the effect of arecoline on rat hepaticdoes not involve transcriptional activation of the gene, but largely involves the stabilization of CYP2E1 protein against degradation or increased efficiency of CYP2E1 mRNA translation, and additionally involve the post- ranslational modification of CYP2E1 protein. Furthermore, the CYP2E1 response is fairly equal among the different species, the induction of rat hepatic CYP2E1 by arecoline suggests that there is a risk of metabolic interaction among the substrate drugs of CYP2E1 in betel-quid use human.
Animals ; Arecoline ; pharmacology ; Cytochrome P-450 CYP2E1 ; metabolism ; Cytochrome P-450 CYP2E1 Inducers ; pharmacology ; Humans ; Liver ; drug effects ; metabolism ; RNA, Messenger ; Rats

Animals ; Cytochrome P-450 CYP2E1 ; biosynthesis ; genetics ; Fatty Liver ; genetics ; Liver ; metabolism ; Male ; Rats ; Rats, Wistar

Cytochrome P-450 CYP2E1 ; metabolism ; Fatty Liver, Alcoholic ; enzymology ; pathology ; Liver ; enzymology

<p>OBJECTIVETo study the effects of salvianolic acid A on content of cytochrome P450,cytochrome b5 and CYP1A2, CYP2E1 activities of rats.p><p>METHODThe rats were randomly divided into two groups and each group contained 5 male rats and 5 female rats. One is control group, another is dosage group. The dosage group was injected salvianolic acid A into a rat tail vein at doses of 20 mg x kg(-1) x d(-1) for 5 days. The control group was injected placebo into a rat tail vein at the same doses as the dosage group. The content of cytochrome P450 and cytochrome b5 of rats were assayed using UV and CYP1A2, CYP2E1 activities were evaluated using probe substrate.p><p>RESULTAfter salvianolic acid A was injected into rats tail vein for 5 days, the total content of cytochrome P450 and cytochrome b5 and CYP1A2 and CYP2E1 activities have no statistical significance of differences than the control group.p><p>CONCLUSIONSalvianolic acid A has no effects on CYP1A2 and CYP2E1 activities, indicating that there is no internation between salvianolic acid A and the drugs metabolized by CYP1A2 or CYP2E1.p>
Animals ; Caffeic Acids ; pharmacology ; Chromatography, High Pressure Liquid ; Cytochrome P-450 CYP1A2 ; metabolism ; Cytochrome P-450 CYP2E1 ; metabolism ; Cytochrome P-450 Enzyme System ; metabolism ; Cytochromes b5 ; metabolism ; Female ; Lactates ; pharmacology ; Male ; Microsomes, Liver ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley

The reasons of same site recurrence in fixed drug eruptions (FDEs) remain to be clarified. Although the nature of antigen in FDE is unknown, drug metabolites could play a role for antigen formation. Cytochrome p450 isozymes (CYPs) are important enzymes for drug metabolism. This study was done to examine the role of CYPs in FDEs. Provoked lesion was compared with non-provoked lesion by the same drug on the same patient to overcome inter-individual variations of CYPs. The reverse transcriptase-polymerase chain reaction (RT-PCR) with primers for CYPs and the immunohistochemistry (IHC) with anti-CYPs, pancytokeratin, and leukocyte common antigen (LCA) antibodies were conducted. The causative drugs were different in 13 patients who conducted RT-PCR, and the result could not be analyzed by the cause. The levels of CYP2C8/19 and CYP2E1 mRNAs increased significantly in provoked lesions. The keratinocytes in cases of mefenamic acid-induced FDEs stained strongly with anti-CYP2C9 antibody not with the other three antibodies (CYP1A1, CYP2E1, and CYP3A4). The FDE cases from doxycycline, which is not metabolized by CYP2C9 enzyme, and those from chlormezanone did not react to anti-CYP2C9 antibody. The cells stained with CYP antibodies did not react with anti-LCA antibody but with anti-pancytokeratin antibody. The number of cells which reacted to anti-LCA antibody clearly increased in the provoked lesions, regardless of the cause. The above results suggest that CYPs may contribute the drug antigen formation and different levels of CYPs between provoked and non-provoked lesions can play a role for the same site recurrence of lesions in FDEs.
Antibodies ; Antigens, CD45 ; Chlormezanone ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Doxycycline ; Drug Eruptions ; Humans ; Immunohistochemistry ; Isoenzymes* ; Keratinocytes ; Metabolism ; Recurrence ; RNA, Messenger

PURPOSE: Interindividual genetic differences in susceptibility to chemical carcinogens are one of the most important host factors in human cancer. The genetically determined differences in metabolism, related to cytochrome P450 (CYP450) genes have been reported to be associated with various cancer susceptibility. The present study was set up to establish the frequency of the polymorphic genotypes of two CYP450 (CYP2E1/PstI and CYP2E1/DraI) isozymes in Korea, to evaluate a possible increased incidence of the genotype associated with higher cervical cancer risks among Korean cervical cancer patients. MATERIALS AND METHODS: In this study, extracted DNAs from 228 cervical cancer patients and 360 normal healthy controls were analysed with the polymerase chain reaction-restriction fragment length polymosphism (PCR-RFLP) method. RESULTS: In the CYP 2E1 genotypes, detected by PstI or RsaI digestion, there were no statistically remarkable differences between the cervical cancer patients and control groups. And when the cervical cancer patients were divided into subgroups with respect to the age, the frequency of CYP 2E1/PstI polymorphisms in the cervical cancer patients under the 40 years old was not significantly higher compared to the controls or the patients above the 40 years old and, c1/c1 genotype was prominent in this type of polymorphism. The frequency of CYP 2E1/DraI polymorphisms in the cervical cancer patients was not significantly higher compared to the controls, and D/D genotype was prominent in this type of polymorphism. In cervical carcinoma, the polymorphic genotypes of CYP 2E1 were not correlated to other parameters including clinical stage, histological tumor type, and degree of differentiation. CONCLUSION: These results suggest that individuals carrying CYP 2E1/PstI (c1/c1) or CYP 2E1/DraI (D/D) alleles are not genetically susceptible to cervical cancer in Korea.
Adult ; Alleles ; Carcinogens ; Cytochrome P-450 CYP2E1* ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Digestion ; DNA ; Genetic Predisposition to Disease* ; Genotype ; Humans ; Incidence ; Isoenzymes ; Korea ; Metabolism ; Uterine Cervical Neoplasms*

Individual susceptibility to cancers may result from several factors including differences in xenobiotics metabolism, DNA repair, altered oncogenes and suppressor genes, and environmental carcinogen exposures. To determine the frequencies of the genotypes of phase I (CYP1A1 and CYP2E1) and phase II (GSTM1 and NAT2) metabolizing enzymes and to identify the high-risk genotypes of these metabolic enzymes to colon cancer in Korean, we have analyzed 113 colorectal cancer patients and corresponding age and sex matched healthy controls using polymerase chain reaction-restriction fragment length polymorphi(PCR-RFLP). In analysis of phase I enzymes, m1/m2, m2/m2 and Val/Val genotypes in CYP1A1 enzyme polymorphisms and C1/C2 genotype in CYP2E1 polymorphism were associated with high relative risks to colorectal cancers (Odds ratio; 1.51, 1.59, 1.76 and 1.38, respectively). Among the phase II enzymes polymorphisms, GSTM (-) genotype of GSTM1 enzyme and slow acetylator (S/S) of NAT2 enzyme had 1.48 and 1.34 times of relative risks to colorectal cancers, respectively. In combined genotyping of phase I enzymes and GSTM1 polymorphisms, the patients with m1/m2 and GSTM (-), Val/Val and GSTM (-), and C1/C2 and GSTM (-) combined genotypes had higher relative risk than the patients with each baseline of combined genotypes (Odds ratio; 2.15, 5.81 and 2.20, respectively). In combined genotyping of phase I enzyme and NAT2 polymorphisms, the combined genotypes of m1/m2 with slow acetylator and C1/C2 with slow acetylator were more susceptible to colorectal cancer (Odds ratio; 3.5 and 4.5, respectively). These results suggest that the combined genotypes of Val/Val and GSTM (-), m1/m2 and slow acetylator, and C1/C2 and slow acetylator were more susceptible to colorectal cancer in Korean. And genotyping of xenobiotics metabolizing enzymes could be useful for predicting an individual susceptibility to colorectal cancer.
Colonic Neoplasms ; Colorectal Neoplasms* ; Cytochrome P-450 CYP1A1 ; Cytochrome P-450 CYP2E1 ; DNA Repair ; Genes, Suppressor ; Genotype ; Humans ; Korea* ; Metabolism ; Oncogenes ; Polymorphism, Genetic* ; Xenobiotics*