Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: A comparison with nonalcoholics

Liangpunsakul, Suthat; Kolwankar, Dhanashri; Pinto, Amar G.; Gorski, J. Christopher; Hall, Stephen D.; Chalasani, Naga

doi:10.1002/hep.20673

Cited by 48 publications

(29 citation statements)

References 29 publications

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“…CYP3A4 but not CYP3A5 expression appeared to be upregulated in the frontal cortex of human alcoholic brain. Previous studies suggested that CYP3A expression is induced by ethanol in liver in vivo and ex vivo in primary hepatocytes (Hoshino and Kawasaki, 1995;Kostrubsky et al, 1995) and in the intestine of moderate alcohol consumers (Liangpunsakul et al, 2005). However, to our knowledge, this is the first report of induction of CYP3A by alcohol in the human brain.…”

Section: Discussionmentioning

confidence: 55%

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

et al. 2013

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Cytochrome P450 enzymes are responsible for the metabolism of most commonly used drugs. Among these enzymes, CYP3A forms mediate the clearance of around 40-50% of drugs and may also play roles in the biotransformation of endogenous compounds. CYP3A forms are expressed both in the liver and extrahepatically. However, little is known about the expression of CYP3A proteins in specific regions of the human brain. In this study, form-selective antibodies raised to CYP3A4 and CYP3A5 were used to characterize the expression of these forms in the human brain. Both CYP3A4 and CYP3A5 immunoreactivity were found to varying extents in the microsomal fractions of cortex, hippocampus, basal ganglia, amygdala, and cerebellum. However, only CYP3A4 expression was observed in the mitochondrial fractions of these brain regions. Nterminal sequencing confirmed the principal antigen detected by the anti-CYP3A4 antibody in cortical microsomes to be CYP3A4. Immunohistochemical analysis revealed that CYP3A4 and CYP3A5 expression was primarily localized in the soma and axonal hillock of neurons and varied according to cell type and cell layer within brain regions. Finally, analysis of the frontal cortex of chronic alcohol abusers revealed elevated expression of CYP3A4 in microsomal but not mitochondrial fractions; CYP3A5 expression was unchanged. The site-specific expression of CYP3A4 and CYP3A5 in the human brain may have implications for the role of these enzymes in both normal brain physiology and the response to drugs.

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Section: Discussionmentioning

confidence: 55%

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

et al. 2013

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“…The ability of alcohol to induce CYP3A in humans is weaker. A recent study indicates that individuals consuming moderate amounts of alcohol have no alteration in hepatic CYP3A activity but reduced midazolam oral bioavailability, possibly as the result of intestinal CYP3A induction (Liangpunsakul et al, 2005). In our study, moderate to heavy chronic alcohol consumption (defined as 14 or more drinks per week) was associated with a small but discernible increase in hepatic CYP3A activity.…”

Section: Pharmacogenetics Of Cyp3a4 and Cyp3a5supporting

confidence: 45%

Factors Influencing Midazolam Hydroxylation Activity in Human Liver Microsomes

Court²,

Greenblatt³

et al. 2006

Drug Metab Dispos

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ABSTRACT:The cytochrome P450 3A (CYP3A) subfamily (mainly CYP3A4 and CYP3A5) is responsible for metabolizing approximately half of currently marketed drugs, but with considerable interindividual variability in expression and function. To investigate factors contributing to this variability, rates of midazolam (MDZ) 1-hydroxylation and CYP3A4 and CYP3A5 protein content were determined using a set of 54 human liver microsomes (HLMs). Genetic factors investigated included CYP3A4 and CYP3A5 single nucleotide polymorphisms (SNPs) and haplotypes, CYP3A4 mRNA alternative splicing, and CYP3A4 transcriptional start and polyadenylation sites. Demographic and environmental factors investigated included age, gender, and histories of smoking and alcohol consumption. MDZ 1-hydroxylation rates varied from 0.025 to 3.106 nmol/min/mg protein, with significant correlation to CYP3A4 protein content (r s ‫؍‬ 0.92, P < 0.001) but less robust correlation to CYP3A5 protein content (r s ‫؍‬ 0.60, P < 0.001). We identified eight CYP3A4 SNPs (five novel) and nine CYP3A5 SNPs (one novel), as well as seven CYP3A4 and two CYP3A5 haplotypes (all novel). No influence of genotype or haplotype on MDZ 1-hydroxylation rate was observed, although CYP3A5*3A (g.6986a>g; g.31611c>t) carriers had lower CYP3A5 protein content compared with noncarriers (P ‫؍‬ 0.004). No alternative splicing of CYP3A4 mRNA was found. Likewise, only a single transcriptional start site and polyadenylation site for CYP3A4 mRNA were identified. Subjects with a history of alcohol consumption had 2.2-fold higher median MDZ 1-hydroxylation (P ‫؍‬ 0.017), whereas no influence of age, gender, or smoking was evident. In conclusion, the investigated genetic factors did not contribute substantially to the large interindividual variability in midazolam hydroxylation, although alcohol consumption has a discernable but modest influence.

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“…It is possible that it may have taken 4 weeks of alcohol consumption to induce other forms of cytochrome P450 that catalyze the 6-hydroxylation of chlorzoxazone, possibly CYP3A (Gorski et al, 1997). However, in one uncontrolled study, moderate alcohol consumption did not increase CYP3A activity (Liangpunsakul et al, 2005).…”

Section: Figmentioning

confidence: 97%

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

Wolf¹,

Wood²,

Allard³

et al. 2007

Drug Metab Dispos

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ABSTRACT:CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(؊/؊) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(؊/؊) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(؊/؊) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(؊/؊) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(؊/؊) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice.Acetaminophen (APAP) is considered to be a relatively safe drug and is widely prescribed and used for its analgesic and antipyretic properties. The first reports of hepatotoxicity in humans resulting from APAP overdose were in 1966 ( Thomson and Prescott, 1966). Today, APAP is a frequent cause of liver failure and the leading cause of death due to accidental and deliberate overdose (for review, see Bromer and Black, 2003). APAP is mainly glucuronidated and sulfated in the liver by phase II metabolic pathways, leading to excretion of the drug. However, APAP is also metabolized by certain forms of cytochromes P450 (P450s) to N-acetyl-p-benzoquinone imine (NAPQI), a highly electrophilic metabolite that is considered to be responsible for triggering the ensuing liver damage. CYP1A2, CYP2E1, and CYP3A are three forms of rat and human P450s active in the conversion of APAP to NAPQI, with CYP2E1 and CYP3A having greater intrinsic activity than CYP1A2 (Patten et al., 1993;Thummel et al., 1993). Reduced glutathione (GSH) reacts with NAPQI, resulting in the inactivation of this reactive metabolite. When GSH levels become depleted, liver damage can occur as a result of the

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Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: A comparison with nonalcoholics

Cited by 48 publications

References 29 publications

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

Factors Influencing Midazolam Hydroxylation Activity in Human Liver Microsomes

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

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