UGT1A1*28 genotype affects the in-vitro glucuronidation of thyroxine in human livers

Objective L-thyroxine (TO, the most widely used drug for hypothyroidism, undergoes glucuronidation by UDP-glucuronosyltransferases. Clinical evidence obtained after the administration of anticonvulsants suggest that glucuronidation may play an important role in T-4 homeostasis in humans. The aims of this study were to determine the T-4 glucuronidation ability of all commercially available human UGTs, and investigate the relationship between genetic polymorphisms in UGT1A1 and UGT1A9 and T-4 glucuronidation in human livers. Methods Glucuronidation of T-4 in human liver microsomes and recombinant UDP-glucuronosyltransferases was measured by high-pressure liquid chromatography. UGT1A1 -53(TA)(6 > 7) (UGT1A1*28) and UGT1A9 -118T(9 > 10) (UGT1A9*1b) variants were genotyped by polymerase chain reaction and sizing. Results A strong correlation was observed between the glucuronidation of T-4 and SN-38, a UGT1A1 substrate (r=0.82, P < 0.0001). A significant trend of decreasing T-4 glucuronide (T(4)G) levels was observed with increasing number of UGT1A1 -53(TA)(7) alleles (P=0.001). Other hepatic UDP-glucuronosyltransferases involved in TA formation are UGT1A3 and UGT1A9. No significant relationship was observed between UGT1A9 -118T(9 > 10) and T-4 glucuronidation activity. T-4 can also undergo glucuronidation by LlGT1A8 and UGT1A10, which are expressed in the gastrointestinal tract (but not the liver) and may be important for first-pass T-4 metabolism. Pharmacogenetics and Genomics 17:619-627 (C) 2007 Lippincott Williams & Wilkins.