Gene expression profiles of drug‐metabolizing enzymes and transporters with an overexpression of hepatocyte growth factor

Abstract

It is important to elucidate the precise mechanism of drug metabolism during hepatic regeneration. Although cytochromes P450 (CYPs) are well known to be down-regulated in growth-stimulated cells, the overall gene expression profile of drug metabolizing enzymes are still not fully understood during hepatic regeneration. In this study, we investigated the gene expression profiles of such enzymes with an overexpression of hepatocyte growth factor (HGF). Gene expression profiles were obtained using the Affymetrix MOE430A GeneChip oligonucleotide microarray by comparing HGF transgenic mice and wild-type mice. HGF produced a general decrease in mice with the expression of CYP isoforms such as Cyp1a2, Cyp2b10, Cyp2c, Cyp2d9, Cyp3a11, Cyp4a10, and Cyp7a1. Some isoforms of alcohol dehydrogenase, aldehyde dehydrogenase, and carboxylesterase also decreased. In the phase II enzymes, some isoforms of glutathione S-transferase and UDP-glucuronosyl transferase showed a reduced expression, although the sulfotransferase did not. In phase III transporters, some organic anion transporter and organic cation transporters were down-regulated. Among the nuclear receptors that are known to regulate the drug-metabolizing enzymes, small heterodimer partner and constitutive androstane receptor were down-regulated with an HGF overexpression. The protein level and enzymatic activity of Cyp2c decreased with an HGF overexpression. We furthermore investigated the inducibility of Cyp2b10 with xenobiotic inducers. Although the basal expression of Cyp2b10 was repressed, the inducibility was not abolished with the HGF overexpression. HGF down-regulated not only CYPs but also some drug-metabolizing enzymes, transporters, and nuclear receptors. We thus have to take in our mind the low basal expression of drug metabolizing enzymes, when treating patients with a regenerative liver state.