Effect of bupropion on CYP2B6 and CYP3A4 catalytic activity, immunoreactive protein and mRNA levels in primary human hepatocytes: comparison with rifampicin

Abstract

Animals treated with multiple doses of bupropion have had increased bupropion clearance or increased liver weight, suggesting induction of drug-metabolizing activity. The possibility of cytochrome p450 (CYP) induction by bupropion (10 microM) was evaluated in-vitro by comparing catalytic activity, immunoreactive protein and CYP mRNA levels from human hepatocytes in primary culture versus cells treated with vehicle (0.5% methanol) and with rifampicin (rifampin) as a positive control. mRNA levels were analysed using a branched DNA luminescent assay. CYP2B6 activity, protein and mRNA levels were increased by 2.5, 1.5 and 2.1 fold, respectively, by 20 microM rifampicin. However, 10 microM bupropion minimally altered CYP2B6 (1.4, 1.1, 0.8 fold). Although CYP3A4 activity, protein, and mRNA levels were increased by 4.0, 2.3, and 14.0 fold, respectively, by 20 microM rifampicin, 10 microM bupropion minimally altered CYP3A4 (1.4, 1.0, 0.8 fold). Rifampicin (20 microM) increased CYP2E1 protein by 2.1 fold, while 10 microM bupropion minimally altered CYP2E1 protein (1.2 fold). Overall, results of this study suggest that multiple doses of bupropion are not likely to induce CYP2B6, 3A4 or 2E1 in-vivo in man.

Evaluation of hepatotoxicity and cholestasis in rats treated with EtOH extract of Fructus Psoraleae

“…The augment of Liver-to-body weight ratio observed in EEFPtreated group in this study might result from the increase of hepatic metabolic enzyme activity which was reported to be under the regulation of orphan nuclear pregnane X receptor (PXR) (Hesse et al, 2003;Honkakoski and Negishi, 2000;Waxman, 1999). In the classic bile acid biosynthetic pathway, cholesterol 7a-hydroxylase (CYP7A1), a microsomal cytochrome P-450, catalyzes the rate-limiting step in bile acid biosynthesis, and is regulated by bile acids and other signaling molecules (Chiang, 2004).…”

HIV/AIDS Patients Display Lower Relative Bioavailability of Efavirenz than Healthy Subjects

“…Rifampicin induces expression and activity of CYP2B6, the main metabolic enzyme for efavirenz. In primary human hepatocytes, the increase in CYP2B6 activity due to rifampicin varies widely from 2.5 fold to 13-fold (85) (86). In vivo, co-administration of efavirenz with rifampicin may lead to 22 -26% reduction in efavirenz plasma exposure (87)(88)(89) , although more recent studies report no significant differences in efavirenz concentrations with or without rifampicin co-treatment (90,91).…”

Stereoselective Metabolism of Bupropion by Cytochrome P4502B6 (CYP2B6) and Human Liver Microsomes

“…CYP2B6 metabolizes as much as 8% of drugs (18). CYP2B6 exhibits interindividual variability in expression and activity (19), and is susceptible to induction and inhibition (14,(20)(21)(22)(23). Bupropion hydroxylation, catalyzed exclusively by CYP2B6, has been used as an in vitro probe to determine CYP2B6 constitutive activity, the influence of genetic polymorphisms, and drug interactions (23)(24)(25)(26)(27).…”