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UGT1A1 and UGT1A9 variants affect thyroxine glucuronidation in human livers
Author(s) -
Yoder Graber A.,
Innocenti F.,
Ramirez J.,
Chen P. X.,
Das S.,
Ratain M. J.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.171
Subject(s) - glucuronidation , gene isoform , chemistry , ugt2b7 , isozyme , microsome , medicine , glucuronosyltransferase , genotype , enzyme , endocrinology , biochemistry , gene , biology
Background/Aims Thyroxine (T 4 ) is prescribed in patients with hypothyroidism, and is known to undergo glucuronidation. Previous studies propose 1A1 and 1A9 as the main isoforms for T 4 G formation, but a complete 1A screening has not been performed. This study aimed to investigate the relevance of genetic polymorphisms in 1A1 and 1A9 and screen all the functional 1A isoforms for T 4 G formation. Methods Thirty human liver microsomes were genotyped for the 1A1 (TA) n and the 1A9 ‐118T 9>10 promoter polymorphisms. cDNA transfected 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9 and 1A10 were screened for T 4 glucuronidation activity and normalized by relative protein expression. T 4 G formation was measured by HPLC. Results There was a significant correlation between both 1A1 (TA) 6>7 and 1A9 ‐118T 9>10 genotypes and T 4 glucuronidation (P<0.01). The highest T 4 G formation was observed with 1A3 followed by 1A8, 1A1, 1A10, 1A9, and 1A7 and was undetectable with 1A4 and 1A6. Conclusions 1A1 (TA) n and the 1A9 ‐118(T) 9>10 promoter polymorphisms affect T 4 glucuronidation rates. Moreover, our data propose 1A3 as another 1A isoform potentially involved in T 4 G formation. Future studies should further characterize the enzyme efficiencies of these UGTs and determine the clinical relevance of these findings. Clinical Pharmacology & Therapeutics (2005) 77 , P73–P73; doi: 10.1016/j.clpt.2004.12.171