Species and sex differences in propofol glucuronidation in liver microsomes of humans, monkeys, rats and mice
Species and sex differences in propofol glucuronidation in liver microsomes of humans, monkeys, rats and mice
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DOI：
10.1691/ph.2015.5525
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发表时间：
2015-07-01
期刊：
影响因子：
1.6
通讯作者：
Hanioka, N.
中科院分区：
文献类型：
--
作者：
Mukai, M.;Isobe, T.;Hanioka, N.
丙泊酚（2，6-二异丙基苯酚）是临床常用的短效麻醉剂，通过UDP-葡萄糖醛酸转移酶（UGT）快速代谢为葡萄糖醛酸苷。在本研究中，在雄性和雌性人类、猴、大鼠和小鼠的肝微粒体中检查了丙泊酚葡萄糖醛酸化。肝微粒体的丙泊酚葡萄糖醛酸化动力学符合人和小鼠的底物抑制模型、猴的Hill模型和大鼠的同工酶（双相）模型。人肝微粒体的Km、V-max和克林特值分别为50 μ M、5.6 nmol/min/mg蛋白和110 μ L/min/mg蛋白（雄性），46 μ M、6.0 nmol/min/mg蛋白和130 μ L/min/mg蛋白（雌性）。雄性和雌性肝微粒体的克林特或CLmax（体外清除率）值的排序均为小鼠>>人>猴>大鼠（高亲和力相）>>大鼠（低亲和力相）。尽管在任何动物种属中未观察到动力学参数值的显著性别差异，但肝微粒体的体外清除率值在人类中为雄性<雌性，在大鼠中为雄性=雌性（低亲和力相），在猴、大鼠（高亲和力相）和小鼠中为雄性>雌性。这些结果表明，人、猴、大鼠和小鼠肝微粒体对丙泊酚葡萄糖醛酸化的动力学特征显著不同，并表明UGT亚型（包括UGT 1A 9）在其代谢中的作用存在种属和性别差异。
Propofol (2,6-diisopropylphenol) is a short-acting anesthetic commonly used in clinical practice, and is rapidly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT). In the present study, propofol glucuronidation was examined in the liver microsomes of male and female humans, monkeys, rats, and mice. The kinetics of propofol glucuronidation by liver microsomes fit the substrate inhibition model for humans and mice, the Hill model for monkeys, and the isoenzyme (biphasic) model for rats. The K-m, V-max, and CLint values of human liver microsomes were 50 mu M, 5.6 nmol/min/mg protein, and 110 mu L/min/mg protein, respectively, for males, and 46 mu M, 6.0 nmol/min/mg protein, and 130 mu L/min/mg protein, respectively, for females. The rank order of the CLint or CLmax (in vitro clearance) values of liver microsomes was mice >> humans > monkeys > rats (high-affinity phase) >> rats (low-affinity phase) in both males and females. Although no significant sex differences were observed in the values of kinetic parameters in any animal species, the in vitro clearance values of liver microsomes were males < females in humans, males = females in rats (low-affinity phase), and males > females in monkeys, rats (high-affinity phase), and mice. These results demonstrated that the kinetic profile of propofol glucuronidation by liver microsomes markedly differed among humans, monkeys, rats, and mice, and suggest that species and sex differences exist in the roles of UGT isoform(s), including UGT1A9, involved in its metabolism.