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Polymorphisms in UDP glucuronosyltransferase genes: functional consequences and clinical relevance
P I Mackenzie1, J O Miners, R A McKinnon
1Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, Adelaide, SA, Australia. Peter.Mackenzie@flinders.edu.au
Clinical Chemistry and Laboratory Medicine
|November 30, 2000
Summary
Genetic variations in UDP glucuronosyltransferases (UGT) impact drug and toxin metabolism. While UGT1A1 polymorphisms affect bilirubin, the clinical significance of other UGT variants remains largely unclear.
Area of Science:
- Pharmacogenomics
- Drug Metabolism
- Biochemistry
Background:
- Glucuronidation is a key pathway for eliminating lipophilic compounds.
- Polymorphisms in UDP glucuronosyltransferase (UGT) genes can alter detoxification capacity.
- Twenty-four human UGT genes are known, but only five have described polymorphisms.
Purpose of the Study:
- To review the known polymorphisms in human UDP glucuronosyltransferase (UGT) genes.
- To discuss the potential clinical significance of these genetic variations in drug and toxin metabolism.
- To highlight the impact of UGT1A1 polymorphisms on bilirubin metabolism.
Main Methods:
- Literature review of identified UDP glucuronosyltransferase (UGT) gene polymorphisms.
- Analysis of clinical implications based on existing research.
- Examination of ethnic variations in polymorphism frequencies.
Main Results:
- Polymorphisms identified in UGT1A1, UGT1A6, UGT2B4, UGT2B7, and UGT2B15.
- UGT1A1 variants are linked to reduced bilirubin glucuronidation (e.g., Gilbert Syndrome).
- Clinical significance of UGT1A6, UGT2B4, UGT2B7, and UGT2B15 variants is currently unclear.
Conclusions:
- UGT1A1 polymorphisms have established clinical relevance, particularly in bilirubin metabolism.
- The clinical impact of polymorphisms in other UGT genes is likely limited unless they are crucial for specific drug metabolism.
- Further discovery of UGT polymorphisms is expected with genome sequencing, but clinical significance will depend on the UGT's role in metabolism.