HUMAN HEPATOCYTE GROWTH-FACTOR DOWN-REGULATES THE EXPRESSION OF CYTOCHROME-P450 ISOZYMES IN HUMAN HEPATOCYTES IN PRIMARY CULTURE

This study examines the effects of recombinant human hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, on the cytochrome P45 0 (CYP) system and conjugating reactions in cultured human hepatocytes . The time course of HGF effects on CYP1A1/2 (7-ethoxyresorufin O-deet hylase) activity revealed that maximal inhibition was observed at 96 h r of culture. HGF produced a general decrease in the activity of all t he CYP isozymes studied, namely CYP1A1/2 (7-ethoxyresorufin O-deethyla se), CYP2B6 (7-benzoxyresorufin O-debenzylase), CYP2A6 (coumarin 7-hyd roxylase), CYP2E1 (p-nitrophenol hydroxylase) and CYP3A4 (testosterone 6 beta-hydroxylase). In contrast, UDP-glucuronyltransferase and gluta thione S-transferase activities and reduced glutathione levels were no t modified significantly by the factor. When hepatocytes were treated with inducers, marked increases in the specific activities of CYP1A1/2 by 3-methylcholanthrene and CYP3A4 by rifampicin were observed, and t hese inductive effects were greatly reduced in the presence of HGF. Fu rthermore, CYP1A2 and CYP3A4 protein levels also dropped in the presen ce of HGF both in control and induced hepatocytes. The observed change s in the activity and protein levels of CYP1A2 and CYP3A4 correlated w ith a reduction in the specific messenger RNA levels both in control, 3-methylcholanthrene-treated (for CYP1A2) and rifampicin-treated (for CYP3A4) hepatocytes, which thus suggested that HGF could down-regulate CYP expression at a pretranslational level.