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

OBJECTIVES: Because shipyard workers are involved with various manufacturing process, they are exposed to many kinds of hazardous materials. Welders especially, are exposed to bisphenol-A (BPA) during the welding and flame cutting of coated steel. This study was conducted to assess the exposure status of the endocrine disruptor based on the job-exposure matrix. The effects of the genetic polymorphism of xenobiotic enzyme metabolisms involved in the metabolism of BPA on the levels of urinary metabolite were investigated. METHODS: The study population was recruited from a shipyard company in the K province. A total of 84 shipbuilding workers 47 and 37 in the exposed and control groups, respectively, were recruited for this study. The questionnaire variables included, age, sex, use of personal protective equipment, smoking, drinking and work duration. The urinary metabolite was collected in the afternoon and correction made for the urinary creatinine concentration. The of the CYP1A1, CYP2E1 and UGT1A6 genotypes were investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods with the DNA extracted from venous blood. RESULTS: The urinary BPA level in the welders group was significantly higher than in the control group (p< 0.05). The urinary BPA concentration with the wild type UGT1A6 was higher than the other UGT1A6 genotypes, but with no statistical significant. From themultiple regression analysis of the urinary BPA, the regression coefficient for job grade was statistically significant (p< 0.05). CONCLUSIONS: The grade of exposure to BPA affected the urinary BPA concentration was statistically significant. However, the genetic polymorphisms of xenobiotics enzyme metabolism were not statistically significant. Further investigation of the genetic polymorphisms with a larger sample size is needed.
Biomarkers* ; Creatinine ; Cytochrome P-450 CYP1A1 ; Cytochrome P-450 CYP2E1 ; DNA ; Drinking ; Genotype ; Hazardous Substances ; Metabolism ; Personal Protective Equipment ; Polymorphism, Genetic ; Sample Size ; Smoke ; Smoking ; Steel ; Welding ; Xenobiotics

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*

This study was carried out to investigate the effect of oral administration of Dendrobium huoshanense on the expressions and activities of hepatic microsomal cytochrome P450s in mice, and to provide a reference for the evaluation of drug-drug interactions between D. huoshanense and clinical drugs. The C57BL/6 mice were randomly divided into blank control group, D. huoshanense low dose group (crude drug 1.25 g·kg⁻¹), D. huoshanense high dose group (crude drug 7.5 g·kg⁻¹), and phenobarbital positive control group (0.08 g·kg⁻¹). Each group was intragastrically administered with drugs for 2 weeks. The mice were sacrificed and their liver microsomes were prepared. The expressions of major subtypes of P450 enzyme were determined by Western blot and the probe drugs were used to detect the enzyme activities of P450 subtypes with protein expression changes. Western blot analysis showed that the protein expressions of CYP1A1, CYP1A2 and CYP2B in liver tissues were up-regulated in D. huoshanense-treated group. In vitro enzyme activity tests showed that there were no significant difference in metabolism of 7-ethoxyresorufin (a probe drug for CYP1A1) and bupropion (a probe drug for CYP2B) between D. huoshanense group and control group. The metabolism of phenacetin (a probe drug for CYP1A2) showed a statistical difference in rate Vmax, and it was significantly increased by approximately 20% in D. huoshanense group as compared with the blank control group, and the clearance CLint in treated group was also increased by about 32%. Therefore, oral administration of D. huoshanense had no effects on the activities of most hepatic P450 enzymes in mice, with no drug-drug interaction related to the P450 enzyme system in most clinical drugs theoretically. However, oral administration of D. huoshanense may accelerate the metabolism of CYP1A2-catalyzed drugs, which needs to be considered in clinical practice.
Animals ; Cytochrome P-450 CYP1A1 ; metabolism ; Cytochrome P-450 CYP1A2 ; metabolism ; Cytochrome P-450 Enzyme System ; metabolism ; Dendrobium ; chemistry ; Drugs, Chinese Herbal ; pharmacology ; Mice ; Mice, Inbred C57BL ; Microsomes, Liver ; drug effects ; enzymology ; Random Allocation

OBJECTIVES: The purpose was to investigate the distributions and the effects of genetic polymorphism of aldehyde dehydrogenase 2(ALDH2), cytochrome P450 1A1(CYP1A1), and cytochrome P450 2E1(CYP2E1) on the toluene metabolism. METHODS: The subjects consisted of 160 workers who were exposed to toluene in different industries such as paint manufacturing, painting on steel and wood products, printing, bonding, and coating. The exposed toluene level was monitored by passive air sampler, and the questionnaire variables were age, sex, smoking, drinking, previous nights drinking, use of personal protective equipment, work duration, and taking benzoic acid containing food. The urinary hippurric acid collected in the end of shift was corrected by urinary creatinine concentration. The genotypes of ALDH2, CYP1A1, and CYP2E1 were investigated using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) methods with DNA extracted from venous blood. RESULTS: The geometric mean and the geometric standard deviation of urinary hippuric acid concentration were 0. 44 g/g creatinine and 2. 80. The urinary hippuric acid concentration was significantly related to personal exposed toluene level among personal exposed toluene level, use of personal protective equipment, and benzoic acid containing food diet. The slope differences of the regression for ALDH2, CYP1A1, and CYP2El genetic polymorphism, age, smoking, and work duration tended to be significant. In multiple regression analysis, the regression coefficient of toluene, ALDH2, CYP1A1, CYP2E1 genetic polymorphism were significant. CONCLUSIONS: Prom the above results, urinary hippuric acid level after toluene exposure was significantly affected by the genetic polymorphism of ALDH2, CYP1A1, CYP2E1. It is needed further investigation of the urinary hippuric acid level considering the effect of genetic polymorphism.
Aldehyde Dehydrogenase ; Benzoic Acid ; Creatinine ; Cytochrome P-450 CYP1A1 ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System ; Diet* ; DNA ; Drinking ; Genotype ; Humans ; Life Style* ; Metabolism ; Paint ; Paintings ; Polymorphism, Genetic ; Questionnaires ; Smoke ; Smoking ; Steel ; Toluene* ; Wood

The effects of styrene on the induction of cytochrome P-450s (P450), (P4501A1/2, P4502B1/2 and P4502El) and activities of other related enzymes were investigated in the male Sprague Dawley rats which were treated with styrene 500 (S1), 1,000 (S2) 1,500 (S3) mg/kg in olive oil intraperitoneally once a day for two days and sacrificed for the preparation of liver microsomes after 24 hrs. 1. The contents of total protein and P450 in the microsomes derived from the styrene treated groups were slightly higher than those from the control group except those from the 53 group (1,500 mg styrene/kg body weight) . The decreases in microsomal protein contents was prominent in the S3 (p<0.05), but the P450 contents was increased significantly in the S2 (p<0.05). 2. The activities of NADPH-P450 and NADH b5 reductase in hepatic microsomes derived from the treated groups were significantly increased in the treated groups(p<0.05). 3. The activities of PROD were also prominently increased with the treatment of styrene except in 53 group, but the activity of EROD was decreased by styrene treatment. The activities of pNPH in the styrene treated groups were higher than that of the control group (p<0.05). 5. Western blotting with monoclonal antibodies against P4502B1/2 isozymes showed the presence of P4502B1/2 in hepatic microsomes from the rats treated with styrene, and the increase in the densities of immunoblots were corelated with the dosages of styrene. The blot densities against P4501A1/2 and P4502El were slightly increased in the styrene treated groups compared with the control group. These results suggested that styrene could primarily induce P4502B1/2 as major and P4501A1/2 and P4502El in minor forms for the metabolism of styrene in rats.
Animals ; Antibodies, Monoclonal ; Blotting, Western ; Cytochrome P-450 CYP1A1 ; Cytochrome P-450 CYP2B1 ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Humans ; Isoenzymes ; Male ; Metabolism ; Microsomes ; Microsomes, Liver ; NAD ; Olea ; Oxidoreductases ; Rats* ; Rats, Sprague-Dawley ; Styrene*

The effects of styrene on the induction of cytochrome P-450s (P450), (P4501A1/2, P4502B1/2 and P4502El) and activities of other related enzymes were investigated in the male Sprague Dawley rats which were treated with styrene 500 (S1), 1,000 (S2) 1,500 (S3) mg/kg in olive oil intraperitoneally once a day for two days and sacrificed for the preparation of liver microsomes after 24 hrs. 1. The contents of total protein and P450 in the microsomes derived from the styrene treated groups were slightly higher than those from the control group except those from the 53 group (1,500 mg styrene/kg body weight) . The decreases in microsomal protein contents was prominent in the S3 (p<0.05), but the P450 contents was increased significantly in the S2 (p<0.05). 2. The activities of NADPH-P450 and NADH b5 reductase in hepatic microsomes derived from the treated groups were significantly increased in the treated groups(p<0.05). 3. The activities of PROD were also prominently increased with the treatment of styrene except in 53 group, but the activity of EROD was decreased by styrene treatment. The activities of pNPH in the styrene treated groups were higher than that of the control group (p<0.05). 5. Western blotting with monoclonal antibodies against P4502B1/2 isozymes showed the presence of P4502B1/2 in hepatic microsomes from the rats treated with styrene, and the increase in the densities of immunoblots were corelated with the dosages of styrene. The blot densities against P4501A1/2 and P4502El were slightly increased in the styrene treated groups compared with the control group. These results suggested that styrene could primarily induce P4502B1/2 as major and P4501A1/2 and P4502El in minor forms for the metabolism of styrene in rats.
Animals ; Antibodies, Monoclonal ; Blotting, Western ; Cytochrome P-450 CYP1A1 ; Cytochrome P-450 CYP2B1 ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Humans ; Isoenzymes ; Male ; Metabolism ; Microsomes ; Microsomes, Liver ; NAD ; Olea ; Oxidoreductases ; Rats* ; Rats, Sprague-Dawley ; Styrene*

metabolism to chemical carcinogens, DNA repair, altered oncogenes and suppressor genes, and environmental carcinogen exposures. Among them, genetic polymorphisms of metabolizing enzymes to chemical carcinogens have been recognized as a major important host factors in human cancers. They have two main types of enzymes: the phase I cytochrome P-450 mediating enzymes (CYPs) and phase II conjugating enzymes. The purpose of this study is to determine the frequencies of genotypes of phase I (CYP1A1 and CYP2E1) and phase II (NAT2) metabolizing enzymes in healthy control and head and neck cancer patients of Korean and to identify the relative high risk genotypes of these metabolizing enzymes to head and neck cancer in Korean. The author has analyzed 132 head and neck cancer patients and 113 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results were as following; 1. The frequencies of genotypes of CYP1A1, CYP2E1 and NAT2 in healthy control were as following; CYP1A1 exon 7 polymorphism; Ile/Ile: Ile/Val: Val/Val = 59.3%: 36.3%: 4.4% CYP2E1 Pst I polymorphism; C1/C1: C1/C2: C2/C2 = 61.1%: 32.1%: 6.2% NAT2 polymorphism; F/F: F/S: S/S = 43.4%: 48.7%: 8.0%. 2. In analysis of phase I enzyme, Val/Val genotype in CYP1A1 exon 7 polymorphism and C2/C2 genotype in CYP2E1 Pst I polymorphism were associated with relative high risks to head and neck cancers (Odds' ratio: 2.09 and 1.37, respectively). 3. Among the genotypes of NAT2 enzyme polymorphism, S/S genotype of NAT2 enzyme had 1.03 times of relative risk to head and neck cancers. 4. In combined genotyping of CYP1A1, CYP2E1, and NAT2 enzymes polymorphisms, the patients with Val/Val and C1/C1, C2/C2 and fast acetylator, and Val/Val and fast acetylator had higher relative risks than the patients with each baseline of combined genotypes (Odds' ratio: 2.82, 1.98 and 2.1, respectively). These results suggest the combined genotypes of Val/Val and C1/C1, C2/C2 and fast acetylator, and Val/Val and fast acetylator were more susceptible to head and neck cancers in Korean. And genotyping of metabolizing enzymes could be useful for predicting individual susceptibility to head and neck cancer.]]>
Carcinogens ; Cytochrome P-450 CYP1A1 ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System ; Cytochromes ; DNA Repair ; Exons ; Genes, Suppressor ; Genetic Predisposition to Disease ; Genotype ; Head and Neck Neoplasms ; Head ; Humans ; Metabolism ; Neck ; Negotiating ; Oncogenes ; Polymorphism, Genetic ; Xenobiotics

Cell Line ; Cytochrome P-450 CYP1A1 ; drug effects ; metabolism ; Hepatocytes ; cytology ; metabolism ; Humans ; Microsomes, Liver ; drug effects ; metabolism ; Quercetin ; pharmacology

Many drugs are primarily metabolized by the cytochrome P450s (CYPs). Drug metabolites would be important allergens for adverse drug reactions such as drug eruptions. Skin tests with a suspected drug have conducted to identify causative drugs of drug eruptions, with vehicles such as white petrolatum, DMSO, ethanol. This study will compare the expression of rat CYP isozyme mRNAs between the skin and the liver, with examining an effect of the vehicles on the cutaneous CYPs using semi-quantitative RT-PCR. Thirty-two Sprague-Dawley rats between the ages of six and eight weeks were divided as four groups. One group was used to compare the constitutive mRNA expression between skin and liver, while the others were to examine the effects of three vehicles. The ratios of expression of CYP1A2, CYP2B1/2, CYP2E1, CYP3A1, and CYP4A1 were significantly higher in the liver than the skin. However, CYP1A1 and CYP2C11 were higher in the skin than liver. The effects of vehicles were quite different; white petrolatum significantly induced CYP1A1 (p=0.012) and CYP2C11 mRNAs, while ethanol inhibited CYP1A1 and CYP2B1/2. DMSO did not make any changes. The results suggest that rat skin can participate in drug metabolism with their own CYP isozymes. The effects of vehicles on the cutaneous CYP expression should not be ignored and may be applied for determination of an appropriate vehicle for certain drug(s).
Allergens ; Animals ; Cytochrome P-450 CYP1A1 ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Dimethyl Sulfoxide* ; Drug Eruptions ; Drug-Related Side Effects and Adverse Reactions ; Ethanol ; Isoenzymes* ; Liver ; Metabolism ; Petrolatum ; Rats* ; Rats, Sprague-Dawley ; RNA, Messenger* ; Skin Tests ; Skin*