Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: a comparison with nonalcoholics.
Alcohol consumption is known to induce hepatic CYP2E1 activity, but its effect on hepatic and intestinal CYP3A in humans is not known. We have conducted a study to compare the CYP2E1 and CYP3A activities in 20 individuals with moderate alcohol consumption and 20 gender-, race-. and body mass index (BMI)-matched nonalcoholics. Intravenous and oral midazolam (MDZ) clearances were used to measure the in vivo CYP3A activity, and chlorzoxazone (CHZ) oral clearance was used to assess in vivo CYP2E1 activity. Furthermore, we assessed the relationship between hepatic CYP2E1 and CYP3A activities and their messenger RNA (mRNA) expression in the peripheral lymphocytes. The systemic clearance (CL) of MDZ was not different between alcoholics (36.9 +/- 12 L/hr) and nonalcoholics (36.6 +/- 14.1; P = .9). The oral availability of MDZ was significantly lower in alcoholics than in the nonalcoholics (0.28 +/- .09 vs. 0.38 +/- .17, respectively, P = .03). The maximum serum concentration after oral midazolam dosing was significantly different between the 2 groups. CHZ CL was significantly higher in alcoholics than in nonalcoholics (31.5 +/- 11.9 vs. 23.4 +/- 8.7 L/hr, P < 0.05). CYP3A4 and CYP2E1 mRNA levels were not significantly different between the groups, and no correlation was observed between lymphocyte CYP mRNA and in vivo CYP activity. In conclusion, in individuals with moderate alcohol consumption, there was no alteration in the hepatic CYP3A activity, but the reduced midazolam oral bioavailability suggests that moderate alcohol consumption may cause intestinal CYP3A induction. Lymphocyte CYP2E1 and CYP3A4 mRNA levels did not correlate with CYP2E1 and CYP3A activities.
Liangpunsakul
Suthat
S
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Kolwankar
Dhanashri
D
Pinto
Amar
A
Gorski
J Christopher
JC
Hall
Stephen D
SD
Chalasani
Naga
N
D000328:Adult; D000428:Alcohol Drinking / Q000378:metabolism*; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002753:Chlorzoxazone / Q000493:pharmacokinetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D005260:Female; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000032:analysis
D014151:Anti-Anxiety Agents; D015415:Biomarkers; D009125:Muscle Relaxants, Central; D012333:RNA, Messenger; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D002753:Chlorzoxazone; D008874:Midazolam