Kaji Hidefumi, Kume Toshiyuki
Exploratory Toxicology & DMPK Research Laboratories, Tanabe Seiyaku Co., LTD., Saitama, Japan.
Drug Metab Pharmacokinet. 2005 Jun;20(3):212-8. doi: 10.2133/dmpk.20.212.
We characterized the hepatic and intestinal UDP-glucuronosyltransferase (UGT) isoform(s) responsible for the glucuronidation of 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetic acid (TA-1801A) in humans through several in vitro mechanistic studies. Assessment of a panel of recombinant UGT isoforms revealed the TA-1801A glucuronosyltransferase activity of UGT1A1, UGT1A3, UGT1A7, UGT1A9, and UGT2B7. Kinetic analyses of the TA-1801A glucuronidation by recombinant UGT1A1, UGT1A3, UGT1A9, and UGT2B7 showed that the K(m) value for UGT2B7 was apparently consistent with those in human liver and jejunum microsomes. The TA-1801A glucuronosyltransferase activity in human liver microsomes was inhibited by bilirubin (typical substrate for UGT1A1), propofol (typical substrate for UGT1A9), diclofenac (substrate for UGT1A9 and UGT2B7), and genistein (substrate for UGT1A1, UGT1A3, and UGT1A9). The inhibition by bilirubin, propofol, and diclofenac of the TA-1801A glucuronidation was less pronounced in jejunum microsomes than liver microsomes, suggesting that the contribution of UGT1A1, UGT1A9, and UGT2B7 to the TA-1801A glucuronidation is smaller in the intestine than the liver. In contrast, genistein strongly inhibited the TA-1801A glucuronosyltransferase activity in both human liver and jejunum microsomes. These results suggest that the glucuronidation of TA-1801A is mainly catalyzed by UGT1A1, UGT1A9, and UGT2B7 in the liver, and by UGT1A1, UGT1A3, and UGT2B7 in the intestine in humans.
我们通过多项体外机制研究，确定了负责人类体内2-(4-氯苯基)-5-(2-呋喃基)-4-恶唑乙酸（TA-1801A）葡萄糖醛酸化的肝脏和肠道UDP-葡萄糖醛酸基转移酶（UGT）同工型。对一组重组UGT同工型的评估显示，UGT1A1、UGT1A3、UGT1A7、UGT1A9和UGT2B7具有TA-1801A葡萄糖醛酸基转移酶活性。对重组UGT1A1、UGT1A3、UGT1A9和UGT2B7催化TA-1801A葡萄糖醛酸化的动力学分析表明，UGT2B7的K(m)值与人类肝脏和空肠微粒体中的K(m)值明显一致。胆红素（UGT1A1的典型底物）、丙泊酚（UGT1A9的典型底物）、双氯芬酸（UGT1A9和UGT2B7的底物）和染料木黄酮（UGT1A1、UGT1A3和UGT1A9的底物）可抑制人类肝脏微粒体中的TA-1801A葡萄糖醛酸基转移酶活性。胆红素、丙泊酚和双氯芬酸对TA-1801A葡萄糖醛酸化的抑制作用在空肠微粒体中比在肝脏微粒体中弱，这表明UGT1A1、UGT1A9和UGT2B7对TA-1801A葡萄糖醛酸化的贡献在肠道中比在肝脏中更小。相比之下，染料木黄酮强烈抑制人类肝脏和空肠微粒体中的TA-1801A葡萄糖醛酸基转移酶活性。这些结果表明，在人类中，TA-1801A的葡萄糖醛酸化在肝脏中主要由UGT1A1、UGT1A9和UGT2B7催化，在肠道中主要由UGT1A1、UGT1A3和UGT2B7催化。
