Genetic variation of human UDP-glucuronosyltransferase: implications in disease and drug glucuronidation.
The uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) are key enzymes in human detoxication of xeno- and endobiotics. Potentially toxic endogenous compounds such as bilirubin, or exogenous compounds such as drugs, pesticides, and carcinogens, are generally transformed into water-soluble glucuronides for excretion in bile and urine. The UGTs are encoded by a multigene family in humans. A relatively small number of human enzymes catalyze the glucuronidation of thousands of compounds. Genetic variations and single nucleotide polymorphisms (SNPs) within the UGT genes are remarkably common, and lead to genetic polymorphisms. The multiplicity of transferases, some exhibiting overlapping substrate specificity, may provide functional compensation for genetic deficit in some cases. Genetic variation may cause different phenotypes by affecting expression levels or activities of individual UGTs. This inter-individual variation in UGTs has resulted in functional deficit affecting endogenous metabolism and leading to jaundice and other diseases. Disruption of the normal metabolic physiology, by the reduction of bile acid excretion or steroid glucuronidation, may lead to cholestasis and organ dysfunction. Deficient glucuronidation of drugs and xenobiotics have an important pharmacological impact, which may lead to drug-induced adverse reactions, and even cancer. Additional novel polymorphisms in this gene family are yet to be revealed and studied, but will have a profound effect on the development of new drugs and therapies.
Burchell
Brian
B
Department of Molecular and Cellular Pathology, Ninewells Medical School, University of Dundee, Dundee, Scotland. b.burchell@dundee.ac.uk
D000818:Animals; D005787:Gene Frequency / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics
D004364:Pharmaceutical Preparations; D014453:Glucuronosyltransferase