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

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.

UDP glucuronosyltransferase mRNA levels in human liver disease.

The UDP glucuronosyltransferases (UGT) are a family of enzymes in which substrates include drugs, xenobiotics, and products of endogenous catabolism. The main source of most UGT enzymes is the liver, a major organ in the detoxification and inactivation of compounds. Previous studies have indicated that glucuronidation, as measured by pharmacokinetic studies, is relatively spared in liver disease.

Impact of a toxicology service on a metropolitan teaching hospital.

Objective: To evaluate the impact of a toxicology service on a major metropolitan teaching hospital.

Method: A descriptive comparative study of all patients presenting with poisoning or suspected poisoning 12 months before and after the commencement of a toxicology service. Data on length of stay in the emergency department, disposition, length of stay of admitted patients and substance(s) involved were examined.

Pharmacotherapeutics: what a difference five decades makes!

Our ability to prevent, cure or modify disease, as compared with relieving symptoms, has changed beyond recognition in the past half century. With the completion of the Human Genome Project and rapid advances in understanding of molecular biology and in technologies, our ability to target disease mechanisms and optimise an individual's responses will improve exponentially.

Bilirubin and bile acids may modulate their own metabolism via regulating uridine diphosphate-glucuronosyltransferase expression in the rat.

Background And Aims: Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) is a critical enzyme in the elimination of bilirubin and it also plays a role in the metabolism of bile acids. The aim of this study was to determine whether bilirubin and bile acids could modulate their own metabolism by regulating UGT levels in cultured rat hepatocytes.

Methods And Results: Incubation of hepatocytes with bilirubin (48 micromol/L) for 24 h significantly increased the mRNA expression of UGT1A1 and UGT1A5, two UGT isoforms responsible for the conjugation of bilirubin.