Assessment of cytochrome P4502E1 induction in alcoholic patients by chlorzoxazone pharmacokinetics

Girre, Catherine; Lucas, Danièle; Hispard, Eric; Ménez, Catherine; Dally, S; Ménez, J. F.

doi:10.1016/0006-2952(94)90524-x

Cited by 151 publications

(93 citation statements)

References 19 publications

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“…The Chlorzoxazone (CZX; Veterans Pharmaceutical, Chung-Li, Taiwan) test was used to determine the enzymatic activity of CYP2E1, as previously described by Girre et al 30 Briefly, after an overnight fasting, healthy volunteers were administered 500 mg of CZX with 200 mL of water. A venous blood sample was drawn 2 hours after drug intake to measure the concentrations of CZX and its metabolite by CYP2E1, 6-hydroxychlorzoxazone (6-OH-CZX), using a high-performance liquid chromatography method as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…A venous blood sample was drawn 2 hours after drug intake to measure the concentrations of CZX and its metabolite by CYP2E1, 6-hydroxychlorzoxazone (6-OH-CZX), using a high-performance liquid chromatography method as previously described. 30 The serum 6-OH-CZX/CZX concentration ratio has been shown to reflect the rate of CZX hydroxylation and thus represent the CYP2E1 activity. [30][31][32] To study the effect of isoniazid on the CYP2E1 activity in subjects with different CYP2E1 genotypes, isoniazid 300 mg daily was administered for 7 days (days 1 to 7).…”

Section: Methodsmentioning

confidence: 99%

“…30 The serum 6-OH-CZX/CZX concentration ratio has been shown to reflect the rate of CZX hydroxylation and thus represent the CYP2E1 activity. [30][31][32] To study the effect of isoniazid on the CYP2E1 activity in subjects with different CYP2E1 genotypes, isoniazid 300 mg daily was administered for 7 days (days 1 to 7). The CZX test was performed 1 day before the administration of isoniazid (day 0) and the last day of isoniazid intake (day 7).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis

Yi¹,

et al. 2003

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Most cases with antituberculosis drug-induced hepatitis have been attributed to isoniazid. Isoniazid is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. However, the role of CYP2E1 in this hepatotoxicity has not yet been reported. The aim of this study was to evaluate whether the polymorphism of the CYP2E1 gene is associated with antituberculosis drug-induced hepatitis. A total of 318 tuberculosis patients who received antituberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Twenty-one healthy volunteers were recruited for CYP2E1 phenotype study using a chlorzoxazone test. Forty-nine (15.4%) patients were diagnosed to have drug-induced hepatotoxicity. Patients with homozygous wild genotype CYP2E1 c1/c1 had a higher risk of hepatotoxicity (20.0%; odds ratio [OR], 2.52) than those with mutant allele c2 (CYP2E1 c1/c2 or c2/c2, 9.0%, P ‫؍‬ .009). If CYP2E1 c1/c2 or c2/c2 genotype combined with rapid acetylator status was regarded as the reference group, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 with rapid acetylator status to 7.43 for CYP2E1 c1/c1 with slow acetylator status. After adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity (OR, 2.38; P ‫؍‬ .017). Furthermore, under the administration of isoniazid, the volunteers with CYP2E1 c1/c1 genotype had higher CYP2E1 activity than those with other genotypes had and, hence, might produce more hepatotoxins. In conclusion, CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis. (HEPATOLOGY 2003;37:924-930.)

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis

Yi¹,

et al. 2003

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“…CHZ, a centrally acting muscle relaxant, is primarily hydroxylated by CYP2E1 to 6-hydroxy CHZ and therefore has been extensively used as a selective probe for measuring hepatic CYP2E1 activity in humans. [17][18][19][20][21] Subjects were asked to avoid certain foods (grapefruit, vegetables from the mustard green family, and beverages containing xanthine and alcohol) for at least 72 hours, and, when possible, nonessential medications were discontinued one week before this test to reduce the chances of drug interference. Blood and urine samples were collected for 8 hours after administering a 500-mg dose of chlorzoxazone orally, followed immediately by 240 mL of water.…”

Section: Methodsmentioning

confidence: 99%

Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis

et al. 2003

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Cytochrome P450 2E1 (CYP2E1) plays an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH) in animal models, but its role in the pathogenesis of human NASH is unclear. Therefore, we measured hepatic CYP2E1 activity and its correlates in a cohort of nondiabetic patients with NASH (NDN) and controls to explore its role in the pathogenesis of human NASH. Hepatic CYP2E1 activity was assessed using the oral clearance (CL PO ) of chlorzoxazone (CHZ) in 20 NDN and 17 age, gender, and body mass index (BMI)-matched controls. The relationship between hepatic CYP2E1 activity and demographic and anthropometric variables; fasting levels of insulin, glucose, lipids, and ␤-OH butyrate; insulin resistance; and nocturnal hypoxemia was assessed. Furthermore, expression of CYP2E1 in the peripheral lymphocytes was assessed using reverse transcription-polymerase chain reaction (RT-PCR). The CL PO of CHZ was significantly (P ‫؍‬ .03) greater in NDN (41 ؎ 12 L/h) compared with controls (33 ؎ 16 L/h). Lymphocyte CYP2E1 messenger RNA was significantly higher in NDN compared with controls (11.5 ؋ 10 3 ؎ 10 ؋ 10 3 vs. 2.6 ؋ 10 3 ؎ 1.2 ؋ 10 3 molecules/ g total RNA, respectively, P < .001). On univariate analysis, BMI, respiratory quotient, high-density lipoprotein, triglycerides, insulin, insulin resistance, hypoxemia, and ␤-OH butyrate significantly correlated with hepatic CYP2E1 activity. However, on stepwise regression analysis, only nocturnal hypoxemia (r ‫؍‬ 0.50, P ‫؍‬ .009) and ␤-OH butyrate (r ‫؍‬ 0.37, P ‫؍‬ .04) were independent predictors of hepatic CYP2E1 activity. In conclusion, hepatic CYP2E1 activity and lymphocyte CYP2E1 expression are enhanced in NDN. The significant correlations noted between CYP2E1 and hypoxemia and ␤-OH butyrate suggest that these factors play a role in increased CYP2E1 activity that is seen in patients with NASH. (HEPATOLOGY 2003;37:544-550.)

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“…by ethanol treatment, and toxicity is reduced by inhibitors of CYP2E1 or in CYP2E1 knockout mice (49). Of the substrates, chlorzoxazone is of special value as its hydroxylated product can readily be assayed in the blood and the ratio of 6-hydroxychlorzoxazone/ chlorzoxazone is widely used to assess the approximate levels of CYP2E1 in humans, including alcoholics (50).…”

Section: Cyp2e1 Substratesmentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

651

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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Assessment of cytochrome P4502E1 induction in alcoholic patients by chlorzoxazone pharmacokinetics

Cited by 151 publications

References 19 publications

Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis

Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis

Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis

CYP2E1 and oxidative liver injury by alcohol

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