Differential regulation of drug transporter expression by hepatocyte growth factor in primary human hepatocytes.

Hepatocyte growth factor (HGF) is known to down-regulate expression of drug-detoxifying proteins such as cytochromes P450 (P450s) in human hepatocytes. The present study was designed to determine whether HGF may also impair expression of uptake and efflux drug transporters, which constitute important determinants of the liver detoxification pathway, such as P450s. Exposure of primary human hepatocytes to 20 ng/ml HGF for 48 h was found to down-regulate mRNA levels of major sinusoidal uptake transporters, including sodium taurocholate-cotransporting polypeptide (NTCP), organic anion-transporting polypeptide (OATP) 2B1, OATP1B1, organic cation transporter (OCT) 1, and organic anion transporter 2. HGF concomitantly reduced NTCP, OATP2B1, and OATP1B1 protein expression and NTCP, OATP, and OCT1 transport activities. With respect to efflux pumps, HGF decreased mRNA expression of the canalicular bile salt export pump, whereas that of the multidrug resistance (MDR) 1 gene was transiently increased. Moreover, Western blot analysis indicated that HGF up-regulated expressions of MDR1/P-glycoprotein and breast cancer resistance protein in human hepatocytes, whereas those of multidrug resistance gene-associated protein (MRP) 2 and MRP3 were unchanged. However, HGF prevented constitutive androstane receptor-related up-regulation of MRP2 occurring in phenobarbital-treated hepatocytes. Taken together, these data demonstrate that HGF differentially regulates transporter expression in human hepatocytes, i.e., it represses most of the sinusoidal uptake transporters, whereas expression of most of the efflux transporters is unchanged or increased. Such changes probably contribute to alterations of pharmacokinetics in patients with diseases associated with increased plasma levels of HGF such as fulminant hepatitis.