Coordinate regulation of metabolic enzymes and transporters by nuclear transcription factors in human liver disease

Abstract

Background: It has been hypothesised, mainly from studies with animal models of liver disease, that the transport of substrates for metabolic enzymes and their subsequent metabolism and elimination in hepatic bile or blood is co-ordinated, but there is little information on this process in diseased human liver.

Methods: In this study we have measured by reverse transcription polymerase chain reaction (RT-PCR) major genes involved in drug metabolism from UDP-glucuronosyltransferases (UGT1A1, UGT1A6, UGT1A9, and UGT2B4) and cytochrome P450 (CYP) families (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), transport (OATP-C, MRP2, MRP3, and MDR1) and major transcription factors (PXR, CAR, HNF1alpha, HNF4alpha, RXR, and AHR) involved in their regulation. Liver biopsy tissue from patients with viral hepatitis was scored for inflammation and fibrosis by the METAVIR system, and separated into groups with mild (A0-1; F0-1, n = 20) or severe (A2-3; F3-4, n = 19) liver disease. Correlation analysis (Spearman rank-test, P < 0.05) was used to identify metabolic enzymes and transporters which shared significant correlation with transcription factors.

Results: Our results show an extensive correlation between transcription factors, transporters, and metabolic enzymes. An unexpected finding was that this was substantially greater in the severely diseased liver. Cross-talk between transcription factors was markedly increased in tissue from patients with severe liver disease, particularly between CAR, HNF4alpha, and PXR.

Conclusion: Our results support the hypothesis of co-ordinate regulation of metabolic enzymes and transporters in diseased human liver, as part of a widespread co-ordinated process under the control of nuclear receptor transcription factors.