An assessment of udp-glucuronosyltransferase induction using primary human hepatocytes
An assessment of udp-glucuronosyltransferase induction using primary human hepatocytes
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DOI：
10.1124/dmd.32.1.140
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发表时间：
2004-01-01
影响因子：
3.9
通讯作者：
Wrighton, SA
中科院分区：
文献类型：
--
作者：
Soars, MG;Petullo, DM;Wrighton, SA
尿苷二磷酸葡萄糖醛酸基转移酶 (UGT) 催化多种外源性底物和内源性底物的葡萄糖醛酸化。然而，缺乏有关人类 UGT 对诱导剂反应的信息，这一观察结果促使了当前的调查。针对一组重组人 UGT 评估雌二醇（3 位和 17 位）、萘酚、丙泊酚和吗啡（3 位和 6 位）的葡萄糖醛酸化，以确定用于诱导研究的选择性葡萄糖醛酸化反应。随后在培养的原代人肝细胞中针对一系列原型诱导剂（包括地塞米松、3-甲基胆蒽 (3-MC)、苯巴比妥、利福平和奥美拉唑）研究了 3 位雌二醇、3 位萘酚、异丙酚和吗啡的葡萄糖醛酸化的潜在诱导作用。在接受调查的 5 名捐赠者中，有 4 名接受 3-MC 治疗后诱导了雌二醇-3-葡萄糖醛酸化（高达 2.5 倍）。卡马西平治疗后观察到萘酚葡萄糖醛酸化显着增加（高达 1.7 倍）。 UGT1A9 介导的丙泊酚葡萄糖醛酸化由苯巴比妥（高达 2.2 倍）和利福平（高达 1.7 倍）诱导。然而，用α-萘黄酮和橘子素治疗导致丙泊酚葡萄糖醛酸化降低（对照值的30%）。在用苯巴比妥、利福平和卡马西平治疗后，至少在三位捐献者中观察到吗啡-3-葡萄糖醛酸化的诱导具有统计学意义。所研究的每种 UGT 同工型都显示出独特的诱导特征。尽管在所研究的每个反应中都观察到葡萄糖醛酸化的统计学显着增加，但诱导水平低于对 CYP1A2 或 CYP3A4 观察到的水平，并且表现出较大的供体间变异性。本研究中获得的诱导反应的临床相关性尚不清楚。
Uridine diphosphate glucuronosyltransferases (UGTs) catalyze the glucuronidation of a wide range of xenobiotics and endogenous substrates. However, there is a lack of information concerning the response of human UGTs to inducers, and this observation prompted the current investigation. The glucuronidation of estradiol (3- and 17-positions), naphthol, propofol, and morphine (3- and 6-positions) was assessed against a battery of recombinant human UGTs to determine selective glucuronidation reactions for induction studies. The potential induction of the glucuronidation of estradiol at the 3-position, naphthol, propofol, and morphine at the 3-position was subsequently investigated in cultured primary human hepatocytes against a range of prototypic inducers including dexamethasone, 3- methylcholanthrene (3-MC), phenobarbital, rifampicin, and omeprazole. Treatment with 3-MC induced estradiol-3-glucuronidation (up to 2.5-fold) in four of five donors investigated. Statistically significant increases in naphthol glucuronidation (up to 1.7-fold) were observed following treatment with carbamazepine. UGT1A9-mediated propofol glucuronidation was induced by phenobarbital (up to 2.2-fold) and rifampicin (up to 1.7-fold). However, treatment with alpha-naphthoflavone and tangeretin resulted in a decrease in propofol glucuronidation (30% of control values). Statistically significant induction of morphine-3-glucuronidation was observed in at least three donors following treatment with phenobarbital, rifampicin, and carbamazepine. Each UGT isoform investigated displayed a distinct induction profile. Although statistically significant increases in glucuronidation were observed for each reaction studied, the level of induction was less than that observed for CYP1A2 or CYP3A4 and exhibited a large interdonor variability. The clinical relevance of the induction responses obtained in this study is unclear.