The pharmacokinetics and macromolecular interactions of trichloroethylene in mice and rats.
The pharmacokinetics and macromolecular interactions of trichloroethylene in mice and rats.
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三氯乙烯在小鼠和大鼠体内的药代动力学和大分子相互作用。
DOI：
10.1016/0041-008x(82)90110-7
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发表时间：
1982
影响因子：
3.8
通讯作者：
P. Watanabe
中科院分区：
文献类型：
--
作者：
W. Stott;J. Quast;P. Watanabe
雄性B6C3F1小鼠比雄性Osborne-Mendel大鼠代谢吸入三氯乙烯(Tri)(600ppm/6小时)更大(262%)。小鼠比大鼠体内代谢更多(332%)吸入TRI为肝脏大分子结合代谢物。在小鼠反复给药试验中，口服TRI导致了与治疗相关的肝细胞毒性。最大耐受量为2400 mg/kg/天的TRI治疗3天的小鼠的肝脏效应主要是小叶中心肝细胞肿胀伴局灶性肝细胞坏死。这些作用导致了再生过程的增强，表现为肝脏DNA合成活性的增加(对照的220%)和有丝分裂图形的发生率。TRI给小鼠(Po)治疗3周(5天/周)后，2400 mg/kg/d剂量组小鼠肝细胞肿胀程度与剂量相关，出现巨大的矿化细胞。对比小鼠的数据，大鼠似乎对最大耐受剂量的TRI不那么敏感，显示出肝脏DNA合成水平的增强(对照组的175%)，但在类似的3周治疗后，每天1100 mg/kg的TRI没有组织病理学。TRI对两种动物的肾组织均无明显影响。对TRI与DNA相互作用程度的估计也是通过测量与纯化的肝DNA相关的放射性确定的。在给予1200 mg/kg tri po的小鼠中，只观察到非常低水平的tri-DNA相互作用，据报道，长期给药会导致肿瘤(最大估计=0.62±0.43烷基化/106个核苷酸)。当在体外诱变试验中结合纯TRI的非常弱的或负的反应时，DNA烷基化数据表明缺乏遗传毒性潜力。总之，这些数据提示B6C3F1小鼠肿瘤形成的表观遗传学机制，这意味着在这些动物中，对TRI暴露的致瘤反应只有在长期给予高细胞毒剂量水平的TRI时才明显。
Male B6C3F1 mice metabolized inhaled trichloroethylene (TRI) (600 ppm/6 hr) to a greater extent (262% more) than male Osborne-Mendel rats. Mice metabolized more (332%) inhaled TRI to a hepatic macromolecular binding metabolite in vivo than rats. Oral administration of TRI resulted in treatment-related hepatocellular cytotoxicity in repeated dosing trials in the mouse. Hepatic effects observed in mice treated with a maximum tolerated dose of 2400 mg/kg/day TRI for 3 days were primarily centrilobular hepatocellular swelling with focal hepatocellular necrosis. These effects lead to an enhanced regenerative process as indicated by increased hepatic DNA synthesis activity (220% of control) and incidence of mitotic figures. Treatment of mice (po) with TRI for a 3-week period (5 days/week) resulted in a dose-related increase in hepatocellular swelling with giant and mineralized cells present in the 2400 mg/kg/day dosed animals. Contrasting the mouse data, rats appeared to be less sensitive to a maximum tolerated dose level of TRI, displaying enhanced hepatic DNA synthesis levels (175% of control) but no histopathology after a similar 3-week treatment with 1100 mg/kg/day TRI. Renal tissue in both species was not significantly affected by TRI. An estimate of the extent of TRI interaction with DNA was also determined by measuring the radioactivity associated with purified hepatic DNA. Only a very low level of in vivo TRI-DNA interaction was observed in mice given 1200 mg/kg TRI po which is reportedly tumorigenic upon chronic administration (maximum estimate = 0.62 ± 0.43 alkylation/106nucleotides). When coupled with the very weak or negative responses of pure TRI in in vitro mutagenesis assays, the DNA alkylation data indicate a lack of genotoxic potential. These data in toto suggest an epigenetic mechanism of tumor formation in the B6C3F1 mouse, implying that a tumorigenic response to TRI exposure in these animals would only be evident upon chronic administration of high, cytotoxic dose levels of TRI.
环氧氯丙烷对非近交系 Sprague-Dawley 大鼠的吸入致癌性。
DOI：
10.1093/jnci/65.4.751
发表时间：
1980
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Laskin,S;Sellakumar,AR;Kuschner,M;Nelson,N;LaMendola,S;Rusch,GM;Katz,GV;Dulak,NC;Albert,RE
通讯作者：
Albert,RE