Variability and Function of Family 1 Uridine-5′-Diphosphate Glucuronosyltransferases (UGT1A)

Abstract

The substrate spectrum of human UDP-glucuronosyltransferase 1A (UGT1A) proteins includes the glucuronidation of non-steroidal anti-inflammatory drugs, anticonvulsants, chemotherapeutics, steroid hormones, bile acids, and bilirubin. The unique genetic organization of the human UGT1A gene locus, and an increasing number of functionally relevant genetic variants define tissue specificity as well as a broad range of interindividual variabilities of glucuronidation. Genetic UGT1A variability has been conserved throughout the protein's evolution and shows ethnic diversity. It is the biochemical and genetic basis for clinical phenotypes such as Gilbert's syndrome and Crigler-Najjar's disease as well as for the potential for severe, unwanted drug side effects such as in irinotecan treatment. UGT1A variants influence the metabolic effects of xenobiotic exposure and therefore have been linked to cancer risk. Detailed knowledge of the organization, function, and pharmacogenetics of the human UGT1A gene locus is likely to significantly contribute to the improvement of drug safety and efficacy as well as to the provision of steps toward the goal of individualized drug therapy and disease risk prediction.

Keywords:

• Pharmacogenetics
• Gilbert's syndrome
• UGT1A7
• carcinogenesis
• drug safety
• glucuronidation
• xenobiotics
• cancer risk
• gene regulation
• single nucleotide polymorphism

Acknowledgment

C. P. S. is supported by the Deutsche Forschungsgemeinschaft (DFG) grants KFO119 project 6, and by SFB621 C3.

Referee Dr. J. Donald Ostrow, Department of Medicine, University of Washington, Seattle, USA