Effect of Nuclear Receptor Downregulation on Hepatic Expression of Cytochrome P450 and Transporters in Chronic Hepatitis C in Association with Fibrosis Development

Abstract

Analysis of mRNAs from liver biopsy samples of patients with chronic hepatitis C revealed that the levels of nuclear receptor expression were correlated with those of drug-metabolizing enzymes and transporters in relation to the development of fibrosis. Overall, the median mRNA level was largely dependent on fibrosis stage (F), and that for stage 3 patients (F3) was about 50% less than that for F1 patients. Levels of expression of AhR, together with CAR and PXR, were lowest in livers of F3 patients. Multivariate linear regression analysis revealed that AhR expression appeared to be involved in the regulation of CYP1A2, 2E1, 2D6, UGT1A, MDR1/3, MRP2/3, NTCP and OCT1 in the livers of patients with chronic hepatitis C. These results suggest that downregulation of AhR during the progression of liver fibrosis is associated with decreased expression levels of these phase I and II enzymes and drug transporters during inflammation-related signal transduction between AhR and other nuclear receptors.

Effect of Liver Disease on Hepatic Transporter Expression and Function

“…Relative mRNA expression of OATP1B1 and OATP2B1 was reduced in the livers of patients with chronic HCV infection, although the mechanistic link between inflammatory cytokines and OATP downregulation is not clear. 108,109 Downregulation of NTCP, OAT2, and OCT1 correlated with fibrosis state, but another study observed no difference compared to control samples. 108,109 In the presence of HCV-induced cirrhosis, expression of NTCP, OATP1B3, and OCT1 are decreased compared to control samples using proteomic analysis.…”

“…108,109 Downregulation of NTCP, OAT2, and OCT1 correlated with fibrosis state, but another study observed no difference compared to control samples. 108,109 In the presence of HCV-induced cirrhosis, expression of NTCP, OATP1B3, and OCT1 are decreased compared to control samples using proteomic analysis. 110 …”

Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

“…Interestingly, a multivariate linear regression analysis revealed that AhR (and PXR) expression might be involved in SLC22A1 gene expression in the livers of patients with chronic hepatitis C. Nevertheless, no direct data indicate the induction of hepatic SLC22A1 gene expression by AhR ligands (Hanada et al, 2012).…”

Comparative pharmacokinetics and tissue distribution profiles of lignan components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe

“…It is reported that the CYP 1A subgroup (a specific isoforms of P450) is significantly reduced in three experimental models of hepatic fibrosis when there is evidence of increased collagen deposition in the livers (Peterson et al, 2000). Not only that, but the expressions of many enzymes and transporters which are related to the internal metabolism and transportation of drugs have remarkably down regulated during the progression of liver fibrosis (Hanada et al, 2012). So, liver fibrosis leading to the change of protein expression and/or activity of most drugs metabolizing enzymes, may have complex effects on drug clearance, biotransformation, pharmacokinetics and tissue distribution.…”