Himmelstein Matthew W, Carpenter Steven C, Hinderliter Paul M
E.I. du Pont de Nemours and Company, Haskell Laboratory for Health and Environmental Sciences, PO Box 50, 1090 Elkton Road, Newark, Delaware 19711, USA.
Toxicol Sci. 2004 May;79(1):18-27. doi: 10.1093/toxsci/kfh092. Epub 2004 Feb 19.
Beta-chloroprene (2-chloro-1,3-butadiene, CD) is carcinogenic by inhalation exposure to B6C3F1 mice and Fischer F344 rats but not to Wistar rats or Syrian hamsters. The initial step in metabolism is oxidation, forming a stable epoxide (1-chloroethenyl)oxirane (1-CEO), a genotoxicant that might be involved in rodent tumorigenicity. This study investigated the species-dependent in vitro kinetics of CD oxidation and subsequent 1-CEO metabolism by microsomal epoxide hydrolase and cytosolic glutathione S-transferases in liver and lung, tissues that are prone to tumor induction. Estimates for Vmax and Km for cytochrome P450-dependent oxidation of CD in liver microsomes ranged from 0.068 to 0.29 micromol/h/mg protein and 0.53 to 1.33 microM, respectively. Oxidation (Vmax/Km) of CD in liver was slightly faster in the mouse and hamster than in rats or humans. In lung microsomes, Vmax/Km was much greater for mice compared with the other species. The Vmax and Km estimates for microsomal epoxide hydrolase activity toward 1-CEO ranged from 0.11 to 3.66 micromol/h/mg protein and 20.9 to 187.6 microM, respectively, across tissues and species. Hydrolysis (Vmax/Km) of 1-CEO in liver and lung microsomes was faster for the human and hamster than for rat or mouse. The Vmax/Km in liver was 3 to 11 times greater than in lung. 1-CEO formation from CD was measured in liver microsomes and was estimated to be 2-5% of the total CD oxidation. Glutathione S-transferase-mediated metabolism of 1-CEO in cytosolic tissue fractions was described as a pseudo-second order reaction; rates were 0.0016-0.0068/h/mg cytosolic protein in liver and 0.00056-0.0022 h/mg in lung. The observed differences in metabolism are relevant to understanding species differences in sensitivity to CD-induced liver and lung tumorigenicity.
β-氯丁二烯（2-氯-1,3-丁二烯，CD）通过吸入暴露可使B6C3F1小鼠和Fischer F344大鼠致癌，但对Wistar大鼠或叙利亚仓鼠不致癌。代谢的初始步骤是氧化，形成稳定的环氧化物（1-氯乙烯基）环氧乙烷（1-CEO），一种可能与啮齿动物致癌性有关的遗传毒性物质。本研究调查了在肝脏和肺这两种易于诱发肿瘤的组织中，微粒体环氧化物水解酶和胞质谷胱甘肽S-转移酶对CD氧化及随后的1-CEO代谢的物种依赖性体外动力学。肝脏微粒体中细胞色素P450依赖性CD氧化的Vmax和Km估计值分别为0.068至0.29微摩尔/小时/毫克蛋白质和0.53至1.33微摩尔。肝脏中CD的氧化（Vmax/Km）在小鼠和仓鼠中略快于大鼠或人类。在肺微粒体中，小鼠的Vmax/Km比其他物种大得多。微粒体环氧化物水解酶对1-CEO的活性的Vmax和Km估计值在不同组织和物种中分别为0.11至3.66微摩尔/小时/毫克蛋白质和20.9至187.6微摩尔。人类和仓鼠肝脏和肺微粒体中1-CEO的水解（Vmax/Km）比大鼠或小鼠更快。肝脏中的Vmax/Km比肺中高3至11倍。在肝脏微粒体中测量了由CD形成1-CEO的情况，估计其占CD总氧化量的2-5%。胞质组织部分中谷胱甘肽S-转移酶介导的1-CEO代谢被描述为拟二级反应；肝脏中的速率为0.0016-0.0068/小时/毫克胞质蛋白质，肺中的速率为0.00056-0.0022/小时/毫克。观察到的代谢差异与理解对CD诱导的肝脏和肺致癌性的敏感性物种差异相关。
