Expression of genes involved in xenobiotic metabolism and transport in end-stage liver disease: up-regulation of ABCC4 and CYP1B1

Pharmacol Rep. 2012;64(4):927-39. doi: 10.1016/s1734-1140(12)70888-5.

Abstract

Background: Expression of drug-metabolizing enzymes and drug transporters in liver is mainly regulated by a system of nuclear receptors. The aim of the current study was to investigate the expression of nuclear receptors, as well as these enzymes and transporters, in liver samples from patients suffering from end-stage liver disease of various etiologies (HCV infection, alcohol liver disease, and primary sclerosis cholangitis).

Methods: Gene expression was measured using quantitative real-time PCR with surgical specimens from livers of patients with end-stage liver disease, and non-tumoral liver tissue that served as control.

Results: Our study confirmed that the expression of most phase I enzymes is suppressed in end-stage liver disease, and is correlated with a decrease in NR1I2 and NR1I3, the main regulators of xenobiotic metabolism. While mRNA levels of phase II enzymes were generally unchanged, some ABC transporters were up-regulated. The most spectacular increases in expression were observed with ABCC4 (MRP4) - at the mRNA level, and CYP1B1 - at both the mRNA and protein levels. We also demonstrated that IL-6 can induce CYP1B1 expression independently of CYP1A1, in a human hepatocellular liver carcinoma cell line.

Conclusions: As CYP1B1 is an enzyme which converts various substrates into carcinogenous metabolites, its overexpression in liver may be one of the factors increasing the risk of hepatic cancers in patients with liver disease. CYP1A1 and CYP1B1 are often referred to as model AHR target genes, but CYP1A1 was down-regulated in diseased liver samples. This points to the existence of differences in regulation of these two genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Biological Transport
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Cytochrome P-450 CYP1A1 / biosynthesis
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1A1 / metabolism
  • Cytochrome P-450 CYP1B1
  • End Stage Liver Disease / enzymology
  • End Stage Liver Disease / genetics*
  • End Stage Liver Disease / metabolism
  • Female
  • Gene Expression
  • Hep G2 Cells
  • Humans
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Liver / metabolism
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Male
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Metabolic Detoxication, Phase I
  • Metabolic Detoxication, Phase II
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / biosynthesis
  • Multidrug Resistance-Associated Proteins / genetics*
  • Multidrug Resistance-Associated Proteins / metabolism
  • Pregnane X Receptor
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Up-Regulation
  • Xenobiotics / metabolism*

Substances

  • ABCC4 protein, human
  • IL6 protein, human
  • Interleukin-6
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • NR1I2 protein, human
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Xenobiotics
  • constitutive androstane receptor
  • Aryl Hydrocarbon Hydroxylases
  • CYP1A1 protein, human
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1B1