Waidyanatha Suramya, Gaudette Norman F, Hong Yan, Fennell Timothy R
Division of National Toxicology Program, National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina 27709, United States.
Chem Res Toxicol. 2014 Oct 20;27(10):1787-95. doi: 10.1021/tx500239q. Epub 2014 Oct 9.
The observed toxicity and carcinogenicity of 1,3-dichloro-2-propanol (DCP) in rodents is thought to be due to the formation of reactive metabolites, epichlorohydrin (ECH) and dichloroacetone (DCA). However, there is no direct evidence for the formation of these metabolites from exposure to DCP in rodents due to the challenges of measuring these reactive intermediates directly in vivo. The objective of this work was to investigate the metabolism of DCP to ECH and DCA in vivo by first developing a sensitive analytical method in a suitable biological matrix and analyzing samples from rats administered DCP. DCA reacted rapidly in vitro in rat blood, plasma, and liver homogenate, precluding its detection. Because ECH rapidly disappeared in liver homogenate, but was relatively long-lived in plasma and blood in vitro, blood was selected for analysis of this metabolite. Following a single oral dose of 50 mg/kg DCP in male or female Harlan Sprague-Dawley rats, ECH was detected in blood with a maximum concentration reached at ≤13.7 min. ECH was cleared rapidly with a half-life of ca. 33 and 48 min in males and females, respectively. Following a single oral dose of 25 mg/kg ECH in male and female rats, the elimination half-life of ECH was ca. 34 and 20 min, respectively; the oral bioavailability of ECH was low (males, 5.2%; females, 2.1%), suggesting extensive first pass metabolism of ECH following oral administration. The area under the concentration vs time curve for ECH following oral administration of DCP and intravenous administration of ECH was used to estimate the percent of the DCP dose converted to ECH in rats. On the basis of this analysis, we concluded that in male and female rats following oral administration of 50 mg/kg DCP, ≥1.26% or ≥1.78% of the administered dose was metabolized to ECH, respectively.
1,3 - 二氯 - 2 - 丙醇（DCP）在啮齿动物中观察到的毒性和致癌性被认为是由于形成了活性代谢产物环氧氯丙烷（ECH）和二氯丙酮（DCA）。然而，由于在体内直接测量这些活性中间体存在挑战，目前尚无直接证据表明啮齿动物接触DCP后会形成这些代谢产物。这项工作的目的是通过首先在合适的生物基质中开发一种灵敏的分析方法，并分析给予DCP的大鼠样本，来研究DCP在体内代谢为ECH和DCA的情况。DCA在大鼠血液、血浆和肝匀浆中体外反应迅速，无法检测到。由于ECH在肝匀浆中迅速消失，但在体外血浆和血液中相对稳定，因此选择血液来分析这种代谢产物。在雄性或雌性哈兰·斯普拉 - 道利大鼠中单次口服50 mg/kg DCP后，血液中检测到ECH，最大浓度在≤13.7分钟时达到。ECH迅速清除，雄性和雌性的半衰期分别约为33分钟和48分钟。在雄性和雌性大鼠中单次口服25 mg/kg ECH后，ECH的消除半衰期分别约为34分钟和20分钟；ECH的口服生物利用度较低（雄性为5.2%；雌性为2.1%），表明口服给药后ECH存在广泛的首过代谢。口服DCP和静脉注射ECH后ECH的浓度 - 时间曲线下面积用于估计大鼠中转化为ECH的DCP剂量百分比。基于此分析，我们得出结论，在雄性和雌性大鼠口服50 mg/kg DCP后，分别有≥1.26%或≥1.78%的给药剂量代谢为ECH。
