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Drug Metabolism and Disposition Fast Forward
First published on October 1, 2007; DOI: 10.1124/dmd.107.018184

0090-9556/08/3601-51-55$20.00
DMD 36:51-55, 2008

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Hepatic UDP-Glucuronosyltransferases Responsible for Glucuronidation of Thyroxine in Humans

Yoshihisa Kato, Shin-ichi Ikushiro, Yoshikazu Emi, Sekihiro Tamaki, Hiroshi Suzuki, Toshiyuki Sakaki, Shizuo Yamada, and Masakuni Degawa

Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa, Japan (Y.K.); Faculty of Engineering, Toyama Prefectural University, Toyama, Japan (S.I., T.S.); Graduate School of Life Science, University of Hyogo, Harima Science Park City, Hyogo, Japan (Y.E.); and School of Pharmaceutical Sciences and Global Center of Excellence Program, University of Shizuoka, Shizuoka, Japan (S.T., H.S., S.Y., M.D.)

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-1{alpha},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.

Address correspondence to: Dr. Yoshihisa Kato, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1 Shido, Sanuki-city, Kagawa 769-2193, Japan. E-mail: kato{at}kph.bunri-u.ac.jp




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J. Guo, A. Liu, H. Cao, Y. Luo, J. M. Pezzuto, and R. B. van Breemen
Biotransformation of the Chemopreventive Agent 2',4',4-Trihydroxychalcone (Isoliquiritigenin) by UDP-Glucuronosyltransferases
Drug Metab. Dispos., October 1, 2008; 36(10): 2104 - 2112.
[Abstract] [Full Text] [PDF]


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