Single-dose disulfiram inhibition of chlorzoxazone metabolism: A clinical probe for P450 2E1

Kharasch, Evan D.; Thummel, Kenneth E.; Mhyre, Jill M.; Lillibridge, James H.

doi:10.1038/clpt.1993.85

Cited by 111 publications

(58 citation statements)

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“…CYP2E1 activity was determined by measuring the hydroxylation of CZX to 6-OH-CZX, as described previously by Kharasch et al (37). All samples were tested in triplicate.…”

Section: Screening For Cyp2e1 Inhibitorsmentioning

confidence: 99%

Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

Shih

Young

Lee

et al. 2013

AAPS J

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Abstract. Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg −1 day −1 . Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31-to 0.48-fold (p<0.005). Mice with INH/RIF-induced hepatotoxicity showed significantly abnormal serum levels of AST and ALT, and GSP value, and these values could be decreased by the administration of kaempferol (p<0.005). Kaempferol significantly reduced the depletion of hepatic glutathione and prevented the increase in MDA formation in mice. Furthermore, kaempferol did not affect the anti-TB effects of INH/RIF. To our knowledge, this is the first report of kaempferol's utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF.

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“…CYP2E1 activity was determined by measuring the hydroxylation of CZX to 6-OH-CZX, as described previously by Kharasch et al (37). All samples were tested in triplicate.…”

Section: Screening For Cyp2e1 Inhibitorsmentioning

confidence: 99%

Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

Shih

Young

Lee

et al. 2013

AAPS J

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“…Activity of CYP2E1 is also modulated by various physiological determinants, such as obesity [7] , fasting [7] and liver dysfunction [8] and can be induced by ethanol [9] . In contrast, dietary isothiocyanates [10] and garlic [11,12] , as well as some drugs, such as disulfiram [13] and chlormethiazole [14] , inhibit its activity. A number of environmental factors may thus modify the cancer risk through altered CYP2E1 enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

CYP2E1 RsaIpolymorphism impacts on risk of colorectal cancer association with smoking and alcohol drinking

Gao

Takezaki²,

Wu³

et al. 2007

WJG

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AIM:To investigate associations between the Rsa Ⅰ polymorphism of CYP2E1 and risk of colorectal cancer. METHODS:A case-control study was conducted with 315 colorectal cancer cases (105 colon, 210 rectal) and 439 population-based controls in Jiangsu Province of China. Genomic DNA samples were assayed for restriction fragment length polymorphisms in CYP2E1 by PCR amplification followed by digestion with Rsa Ⅰ. Information on smoking and alcohol drinking was collected using a questionnaire. Odds ratios (ORs) were estimated with an unconditional logistic model. RESULTS:The proportional distribution of the CYP2E1 Rsa Ⅰc1/c1, c1/c2 and c2/c2 genotypes were 61.4%, 35.6% and 3.0% in controls, 60.6%, 33.7% and 5.8% in colon cancer cases, and 58.4%, 34.0% and 7.7% in rectal cancer cases, respectively. A significant difference was noted between controls and rectal cancer cases (P = 0.029), the c2/c2 genotype being associated with elevated OR (adjusted age, sex and status of the smoking and alcohol drinking) for rectal cancer (1.64, 95% CI, 1.12-2.41, vs c1 allele carriers), but not for colon cancer. In interaction analysis between the CYP2E1 Rsa Ⅰgenotype and smoking and drinking habits, we found a significant cooperative action between the c2/c2 genotype and alcohol drinking in the sex-, age-adjusted ORs for both colon (4.74, 95% CI, 1.10-20.40) and rectal (5.75, 95% CI, 1.65-20.05) cancers. Among nonsmokers, the CYP2E1 Rsa Ⅰc2/c2 genotype was also associated with elevated ORs in the two sites (1.95, 95% CI, 0.99-3.86 and 2.30, 95% CI, 1.32-3.99). CONCLUSION:The results of the present study suggest that the CYP2E1 c2/c2 genotype increases susceptibility to rectal cancer and the gene-environmental interactions between the CYP2E1 polymorphism and smoking or alcohol drinking exist for colorectal neoplasia in general.

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“…Moreover, a previous study has shown that the activity of CYP2E1 is modulated by various physiological determinants, such as obesity (O'Shea et al, 1994), fasting (O'Shea et al, 1994), and liver dysfunction (Dilger et al, 1997), and can be induced by ethanol (Girre et al, 1994). In contrast, dietary isothiocyanates (Leclercq et al, 1998), and garlic (Reicks and Crankshaw, 1996;Yang et al, 1994), as well as some drugs, such as disulfiram (Kharasch et al, 1993), and chlormethiazole (Gebhardt et al, 1997), inhibit CYP2E1 activity.…”

Section: Discussionmentioning

confidence: 99%

Identification of Polymorphisms in CYP2E1 Gene and Association Analysis among Chronic HBV Patients

Chun¹,

Park²,

Cheong³

et al. 2009

Genomics & Informatics

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Cytochrome P450 2E1 (CYP2E1) is a member of the cytochrome P450 superfamily, and it is a key enzyme responsible for the metabolic activation of many smallmolecular-weight compounds such as alcohol, which is classified as a human carcinogen. In this study, we identified 19 single nucleotide polymorphisms (SNPs) in CYP2E1 in Korean population. In these SNPs, we examined possible genetic association of CYP2E1 polymorphisms with HBV clearance and the risk of hepatocellular carcinoma (HCC). Five common polymorphic sites were selected, CYP2E1 polymorphisms at rs381-3867, rs3813870, rs2070673, rs2515641 and rs2480257, considering their allele frequencies, haplotype-tagging status and LDs for genotyping in larger-scale subjects (n=1,092). Statistical analysis demonstrated that CYP2E1 polymorphisms and haplotypes show no significant association with HBV clearance, HCC occurrence and onset age of HCC (p＞0.05). Previous studies, however, have shown contradictory findings on associations of CYP2E1 polymorphisms with CYP2E1 activities and HCC risk. Comparing the contrasting results of previous researches suggest that CYP2E1 polymorphism is associated with CYP2E1 activity induced by ethanol, but is not directly associated with HCC risk. CYP2E1 variation/haploype information identified in this study will provide valuable information for future studies on CYP2E1.

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Single-dose disulfiram inhibition of chlorzoxazone metabolism: A clinical probe for P450 2E1

Cited by 111 publications

References 0 publications

Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

CYP2E1 RsaIpolymorphism impacts on risk of colorectal cancer association with smoking and alcohol drinking

Identification of Polymorphisms in CYP2E1 Gene and Association Analysis among Chronic HBV Patients

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