RT Journal Article
SR Electronic
T1 Hepatic UDP-Glucuronosyltransferases Responsible for Glucuronidation of Thyroxine in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 51
OP 55
DO 10.1124/dmd.107.018184
VO 36
IS 1
A1 Kato, Yoshihisa
A1 Ikushiro, Shin-ichi
A1 Emi, Yoshikazu
A1 Tamaki, Sekihiro
A1 Suzuki, Hiroshi
A1 Sakaki, Toshiyuki
A1 Yamada, Shizuo
A1 Degawa, Masakuni
YR 2008
UL http://dmd.aspetjournals.org/content/36/1/51.abstract
AB To clarify the UDP-glucuronosyltransferase (UGT) isoform(s) responsible for the glucuronidation of the thyroid hormone thyroxine (T4) in the human liver, the T4 glucuronidation activities of recombinant human UGT isoforms and microsomes from seven individual human livers were comparatively examined. Among the 12 recombinant human UGT1A and UGT2B subfamily enzymes examined, UGT1A1, UGT1A3, UGT1A9, and UGT1A10 showed definite activities for T4 glucuronidation. These UGT1A enzymes, with the exception of UGT1A10, were detected in all of the human liver microsomes examined. Interindividual differences in T4 glucuronidation activity were observed among the microsomes from the seven individual human livers, and the T4 glucuronidation activity was closely correlated with β-estradiol 3-glucuronidation activity. Furthermore, Spearman correlation analysis for a relationship between the T4 glucuronidation activity and the level of UGT1A1, UGT1A3, and UGT1A9 in the microsomes revealed that levels of UGT1A1 and UGT1A3, but not that of UGT1A9, were closely correlated with T4 glucuronidation activity. T4 glucuronidation activity in human liver microsomes was strongly inhibited by 26,26,26,27,27,27-hexafluoro-1α,23(S),25-trihydroxyvitamin D3 (an inhibitor of UGT1A3), moderately inhibited by either bilirubin (an inhibitor of UGT1A1) or β-estradiol (an inhibitor of UGT1A1 and UGT1A9), but not inhibited by propofol (an inhibitor of UGT1A9). These findings indicated strongly that glucuronidation of T4 in the human liver was mediated by UGT1A subfamily enzymes, especially UGT1Al and UGT1A3, and further suggested that the interindividual differences would come from differences in the expression levels of UGT1A1 and UGT1A3 in individual human livers. The American Society for Pharmacology and Experimental Therapeutics