Family 1 uridine-5'-diphosphate glucuronosyltransferases (UGT1A): from Gilbert's syndrome to genetic organization and variability.
The human UDP-glucuronosyltransferase 1A gene locus is organized to generate enzymes, which share a carboxyterminal portion and are unique at their aminoterminal variable region. Expression is tissue-specific and overlapping substrate specificities include a broad spectrum of endogenous and xenobiotic compounds as well as many therapeutic drugs targeted for detoxification and elimination by glucuronidation. The absence of glucuronidation leads to fatal hyperbilirubinemia. A remarkable interindividual variability of UDP-glucuronosyltransferases is evidenced by over 100 identified genetic variants leading to alterations of catalytic activites or transcription levels. Variant alleles with lower carcinogen detoxification activity have been associated with cancer risk such as colorectal cancer and hepatocellular carcinoma. Genetic variants and haplotypes have been identified as risk factors for unwanted drug effects of the anticancer drug irinotecan and the antiviral proteinase inhibitor atazanavir. Glucuronidation and its variability are likely to represent an important factor for individualized drug therapy and risk prediction impacting the drug development and licensing processes.
Strassburg
Christian P
CP
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. strassburg.christian@mh-hannover.de
Lankisch
Tim O
TO
Manns
Michael P
MP
Ehmer
Ursula
U
D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives / Q000633:toxicity; D014644:Genetic Variation; D005878:Gilbert Disease / Q000150:complications / Q000201:enzymology* / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D007527:Isoenzymes / Q000145:classification / Q000235:genetics / Q000378:metabolism; D007565:Jaundice / Q000139:chemically induced; D009369:Neoplasms / Q000150:complications / Q000453:epidemiology; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use; D010597:Pharmacogenetics; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use; D012307:Risk Factors; D009626:Terminology as Topic; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D000069446:Atazanavir Sulfate; D001663:Bilirubin; D002166:Camptothecin; D014453:Glucuronosyltransferase; D017320:HIV Protease Inhibitors; D000077146:Irinotecan; D007527:Isoenzymes; D009842:Oligopeptides; D011725:Pyridines; D000099148:UGT1A1 Enzyme