Seng John E, Agrawal Nalini, Horsley Elizabeth T M, Leakey Tatiana I, Scherer Erin M, Xia Shijun, Allaben William T, Leakey Julian E A
National Center for Toxicological Research, Jefferson, AR 72079, USA.
Toxicol Appl Pharmacol. 2003 Dec 1;193(2):281-92. doi: 10.1016/j.taap.2003.07.008.
Chloral hydrate is widely used as a sedative in pediatric medicine and is a by-product of water chlorination and a metabolic intermediate in the biotransformation of trichloroethylene. Chloral hydrate and its major metabolite, trichloroacetic acid, induce liver tumors in B6C3F1 mice, a strain that can exhibit high rates of background liver tumor incidence, which is associated with increased body weight. This report describes the influence of diet and body weight on the acute toxicity, hepatic enzyme response, and toxickinetics of chloral hydrate as part of a larger study investigating the carcinogenicity of chloral hydrate in ad libitum-fed and dietary controlled mice. Dietary control involves moderate food restriction to maintain the test animals at an idealized body weight. Mice were dosed with chloral hydrate at 0, 50, 100, 250, 500, and 1000 mg/kg daily, 5 days/week, by aqueous gavage for 2 weekly dosing cycles. Three diet groups were used: ad libitum, dietary control, and 40% caloric restriction. Both dietary control and caloric restriction slightly reduced acute toxicity of high doses of chloral hydrate and potentiated the induction of hepatic enzymes associated with peroxisome proliferation. Chloral hydrate toxicokinetics were investigated using blood samples obtained by sequential tail clipping and a microscale gas chromatography technique. It was rapidly cleared from serum within 3 h of dosing. Trichloroacetate was the major metabolite in serum in all three diet groups. Although the area under the curve values for serum trichloroacetate were slightly greater in the dietary controlled and calorically restricted groups than in the ad libitum-fed groups, this increase did not appear to completely account for the potentiation of hepatic enzyme induction by dietary restriction.
水合氯醛在儿科学中被广泛用作镇静剂，它是水氯化的副产物，也是三氯乙烯生物转化过程中的代谢中间体。水合氯醛及其主要代谢产物三氯乙酸可在B6C3F1小鼠中诱发肝肿瘤，该品系小鼠背景肝肿瘤发生率较高，且这与体重增加有关。本报告描述了饮食和体重对水合氯醛急性毒性、肝酶反应及毒代动力学的影响，这是一项关于水合氯醛对自由采食和饮食控制小鼠致癌性的更大规模研究的一部分。饮食控制包括适度限制食物摄入，以使实验动物维持在理想体重。小鼠每天按0、50、100、250、500和1000 mg/kg的剂量经水灌胃给予水合氯醛，每周5天，共进行2个每周给药周期。使用了三个饮食组：自由采食、饮食控制和40%热量限制。饮食控制和热量限制均略微降低了高剂量水合氯醛的急性毒性，并增强了与过氧化物酶体增殖相关的肝酶诱导作用。采用连续剪尾采血和微量气相色谱技术获取血样，研究水合氯醛的毒代动力学。给药后3小时内，水合氯醛迅速从血清中清除。三氯乙酸是所有三个饮食组血清中的主要代谢产物。尽管饮食控制组和热量限制组血清三氯乙酸的曲线下面积值比自由采食组略大，但这种增加似乎并未完全解释饮食限制对肝酶诱导的增强作用。
