Department of Clinical Pharmacology, College of Medicine, The University of Arizona, P.O. Box 245050, Tucson, AZ 85724-5050, USA.
Drug Metab Dispos. 2010 Jun;38(6):957-62. doi: 10.1124/dmd.110.032110. Epub 2010 Mar 3.
2,2-Bis(bromomethyl)-1,3-propanediol (BMP) is a brominated flame retardant used in unsaturated polyester resins. In a 2-year bioassay BMP was shown to be a multisite carcinogen in rats and mice. Because glucuronidation is the key metabolic transformation of BMP by rats, in this study the in vitro hepatic glucuronidation of BMP was compared across several species. In addition, the glucuronidation activities of human intestinal microsomes and specific human hepatic UDP-glucuronosyltransferase (UGT) enzymes for BMP were determined. To explore other possible routes of metabolism for BMP, studies were conducted with rat and human hepatocytes. Incubation of hepatic microsomes with BMP in the presence of UDP-glucuronic acid resulted in the formation of a BMP monoglucuronide. The order of hepatic microsomal glucuronidation activity of BMP was rats, mice >> hamsters > monkeys >>> humans. The rate of glucuronidation by rat hepatic microsomes was 90-fold greater than that of human hepatic microsomes. Human intestinal microsomes converted BMP to BMP glucuronide at a rate even lower than that of human hepatic microsomes. Among the human UGT enzymes tested, only UGT2B7 had detectable glucuronidation activity for BMP. BMP monoglucuronide was the only metabolite formed when BMP was incubated with suspensions of freshly isolated hepatocytes from male F-344 rats or with cryopreserved human hepatocytes. Glucuronidation of BMP in human hepatocytes was extremely low. Overall, the results support in vivo studies in rats in which BMP glucuronide was the only metabolite found. The poor glucuronidation capacity of humans for BMP suggests that the pharmacokinetic profile of BMP in humans will be dramatically different from that of rodents.
2,2-双（溴甲基）-1,3-丙二醇（BMP）是一种用于不饱和聚酯树脂的溴化阻燃剂。在为期两年的生物测定中，BMP 被证明是大鼠和小鼠的多部位致癌物质。由于葡萄糖醛酸化是大鼠对 BMP 的关键代谢转化，因此在这项研究中比较了几种物种的体外肝葡萄糖醛酸化。此外，还测定了人肠微粒体和特定人肝 UDP-葡萄糖醛酸转移酶（UGT）对 BMP 的葡萄糖醛酸化活性。为了探索 BMP 其他可能的代谢途径，对大鼠和人肝细胞进行了研究。在存在 UDP-葡萄糖醛酸的情况下孵育肝微粒体与 BMP 导致形成 BMP 单葡萄糖醛酸苷。BMP 肝微粒体葡萄糖醛酸化活性的顺序为大鼠、小鼠>仓鼠>猴子>人类。大鼠肝微粒体的葡萄糖醛酸化速率比人肝微粒体高 90 倍。人肠微粒体将 BMP 转化为 BMP 葡萄糖醛酸苷的速率甚至低于人肝微粒体。在所测试的人 UGT 酶中，只有 UGT2B7 对 BMP 具有可检测的葡萄糖醛酸化活性。当 BMP 与雄性 F-344 大鼠新鲜分离的肝细胞悬浮液或冷冻保存的人肝细胞孵育时，仅形成 BMP 单葡萄糖醛酸苷。人肝细胞中 BMP 的葡萄糖醛酸化极低。总的来说，这些结果支持了大鼠体内研究，其中 BMP 葡萄糖醛酸苷是唯一发现的代谢物。人对 BMP 的葡萄糖醛酸化能力差表明，BMP 在人体内的药代动力学特征将与啮齿动物明显不同。
