Effect of interferon-alpha2b on the expression of various drug-metabolizing enzymes and transporters in co-cultures of freshly prepared human primary hepatocytes.

摘要

The purpose of this study was to assess the impact of interferon-alpha2b (IFN-alpha2b) on the expression of various drug-metabolizing enzymes and transporters in freshly prepared co-cultures (parenchymal and non-parenchymal cells) of human primary hepatocytes. At therapeutically relevant concentrations (from 1000 to 3000 IU/mL), IFN-alpha2b up-regulated STAT1 (signal transducer and activator of transcription factor 1) mRNA expression. Conversely, three cytochrome P450s (CYP1A2, CYP2B6, CYP2E1), a UDP-glucuronosyltransferase (UGT2B7), a sulphotransferase (SULT1A1) and organic anion transporter (OAT2) were significantly down-regulated (~50%; P < 0.05). Western blot analysis of CYP1A2, UGT2B7 and OAT2 protein supported the mRNA data. Two peroxisome proliferator activator receptor alpha (PPARalpha)-controlled genes (pyruvate dehydrogenase kinase 4 and adipose differentiation-related protein), CYP3A4 and multidrug resistance-associated protein 2 were significantly up-regulated (up to 223%; P < 0.05). On the other hand, SULT2A1, carboxylesterase 2, organic anion transporting peptide (OATP1B1, OATP1B3, OATP2B1), organic cation transporter 1, P-glycoprotein and breast cancer resistance protein mRNA expression was not significantly affected. Western blot analysis of CYP3A4 supported the mRNA data also. The present results demonstrated complex interactions between IFN-alpha2b and hepatocytes and the observed down-regulation of CYP1A2, OAT2 and UGT2B7 is consistent with reports of drug interactions between IFN-alpha2b and drugs such as theophylline, clozapine and gemfibrozil.