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Drug Metabolism and Disposition Fast Forward
First published on June 25, 2007; DOI: 10.1124/dmd.107.016097

0090-9556/07/3509-1642-1648$20.00
DMD 35:1642-1648, 2007

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Glucuronidation of Thyroxine in Human Liver, Jejunum, and Kidney Microsomes

Hiroyuki Yamanaka, Miki Nakajima, Miki Katoh, and Tsuyoshi Yokoi

Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

Glucuronidation of thyroxine is a major metabolic pathway facilitating its excretion. In this study, we characterized the glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes, and identified human UDP-glucuronosyltransferase (UGT) isoforms involved in the activity. Human jejunum microsomes showed a lower Km value (24.2 µM) than human liver (85.9 µM) and kidney (53.3 µM) microsomes did. Human kidney microsomes showed a lower Vmax value (22.6 pmol/min/mg) than human liver (133.4 pmol/min/mg) and jejunum (184.6 pmol/min/mg) microsomes did. By scaling-up, the in vivo clearances in liver, intestine, and kidney were estimated to be 1440, 702, and 79 µl/min/kg body weight, respectively. Recombinant human UGT1A8 (108.7 pmol/min/unit), UGT1A3 (91.6 pmol/min/unit), and UGT1A10 (47.3 pmol/min/unit) showed high, and UGT1A1 (26.0 pmol/min/unit) showed moderate thyroxine glucuronosyltransferase activity. The thyroxine glucuronosyltransferase activity in microsomes from 12 human livers was significantly correlated with bilirubin O-glucuronosyltransferase (r = 0.855, p < 0.001) and estradiol 3-O-glucuronosyltransferase (r = 0.827, p < 0.0001) activities catalyzed by UGT1A1, indicating that the activity in human liver is mainly catalyzed by UGT1A1. Kinetic and inhibition analyses suggested that the thyroxine glucuronidation in human jejunum microsomes was mainly catalyzed by UGT1A8 and UGT1A10 and to a lesser extent by UGT1A1, and the activity in human kidney microsomes was mainly catalyzed by UGT1A7, UGT1A9, and UGT1A10. The changes of activities of these UGT1A isoforms via inhibition and induction by administered drugs as well as genetic polymorphisms may be a causal factor of interindividual differences in the plasma thyroxine concentration.

Address correspondence to: Dr. Tsuyoshi Yokoi, Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. E-mail: tyokoi{at}kenroku.kanazawa-u.ac.jp




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Y. Kato, S.-i. Ikushiro, Y. Emi, S. Tamaki, H. Suzuki, T. Sakaki, S. Yamada, and M. Degawa
Hepatic UDP-Glucuronosyltransferases Responsible for Glucuronidation of Thyroxine in Humans
Drug Metab. Dispos., January 1, 2008; 36(1): 51 - 55.
[Abstract] [Full Text] [PDF]


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