Glucuronidation of thyroxine in human liver, jejunum, and kidney Microsomes
Glucuronidation of thyroxine in human liver, jejunum, and kidney Microsomes
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DOI：
10.1124/dmd.107.016097
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发表时间：
2007-09-01
影响因子：
3.9
通讯作者：
Yokoi, Tsuyoshi
中科院分区：
文献类型：
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作者：
Yamanaka, Hiroyuki;Nakajima, Miki;Yokoi, Tsuyoshi
甲状腺素的葡萄糖醛酸化是促进其排泄的主要代谢途径。在这项研究中，我们的特点是甲状腺素的葡萄糖醛酸化在人类肝脏，空肠，和肾脏微粒体，并确定人类UDP-葡萄糖醛酸转移酶（UGT）亚型参与的活动。人空肠微粒体的Km值（24.2 μ M）低于人肝（85.9 μ M）和肾（53.3 μ M）微粒体。人肾微粒体的V-max值（22.6 pmol/min/mg）低于人肝微粒体（133.4 pmol/min/mg）和空肠微粒体（184.6 pmol/min/mg）。通过按比例放大，肝、肠和肾中的体内清除率估计分别为1440、702和79 μ l/ min/kg体重。重组人UGT 1A 8（108.7 pmol/min/单位）、UGT 1A 3（91.6 pmol/min/单位）和UGT 1A 10（47.3 pmol/min/单位）显示较高活性，UGT 1A 1（26.0 pmol/min/单位）显示中度甲状腺素葡萄糖醛酸基转移酶活性。12例人肝脏微粒体中的甲状腺素葡萄糖醛酸转移酶活性与UGT 1A 1催化的胆红素O-葡萄糖醛酸转移酶（r = 0.855，p < 0.001）和雌二醇3-O-葡萄糖醛酸转移酶（r = 0.827，p < 0.0001）活性显著相关，表明人肝脏中的活性主要由UGT 1A 1催化。动力学和抑制分析表明，人空肠微粒体中的甲状腺素葡萄糖醛酸化主要由UGT 1A 8和UGT 1A 10催化，UGT 1A 1在较小程度上催化，人肾微粒体中的活性主要由UGT 1A 7、UGT 1A 9和UGT 1A 10催化。这些UGT 1A异构体的活性变化，通过抑制和诱导给药的药物以及遗传多态性可能是一个因果关系的血浆甲状腺素浓度的个体间差异的因素。
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 mu M) than human liver ( 85.9 mu M) and kidney ( 53.3 mu M) microsomes did. Human kidney microsomes showed a lower V-max 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 mu l/ 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.