Weber G L, Sipes I G
Department of Pharmacology/Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.
Toxicol Appl Pharmacol. 1990 Jul;104(3):395-402. doi: 10.1016/0041-008x(90)90161-m.
Preliminary investigations into the role of biotransformation in 1,2,3-trichloropropane (TCP)-induced tumor formation have been undertaken. Male F-344 rats were administered 30 mg/kg [14C]TCP (100 microCi/kg) ip and killed 4 hr later. The extent of covalent binding to hepatic protein, DNA, and RNA was 418, 244, and 432 pmol [14C]TCP equivalents/mg, respectively. An in vivo covalent binding time course showed no significant change in [14C]TCP equivalents bound to hepatic DNA (1-48 hr), while binding to protein was maximal by 4 hr and decreased significantly by 48 hr. The binding of TCP-associated radioactivity to hepatic protein and DNA was shown to be cumulative for two and three doses when given 24 hr apart. Pretreatment of animals with phenobarbital caused a decrease while pretreatment with SKF 525-A caused an increase in covalent binding of [14C]TCP equivalents to protein and DNA. Pretreatment of rats with beta-naphthoflavone did not alter the covalent binding of [14C]TCP equivalents to protein or DNA. However, glutathione depletion with L-buthionine-(R,S)-sulfoximine increased binding to protein by 342% while it decreased binding to DNA by 56%. Intraperitoneal administration of TCP also depleted hepatic GSH by 41 and 61% 2 hr after doses of 30 and 100 mg/kg. The in vivo binding data suggest a dual role for GSH in the bioactivation of TCP. It may, in part, be that GSH is involved in the bioactivation and covalent binding of TCP to hepatic DNA. However, it also appears to detoxify a reactive intermediate(s) that binds to protein.
已对生物转化在1,2,3 - 三氯丙烷（TCP）诱导肿瘤形成中的作用进行了初步研究。给雄性F - 344大鼠腹腔注射30 mg/kg [¹⁴C]TCP（100 μCi/kg），4小时后处死。与肝蛋白、DNA和RNA的共价结合程度分别为418、244和432 pmol [¹⁴C]TCP当量/mg。体内共价结合时间进程显示，与肝DNA结合的[¹⁴C]TCP当量在1 - 48小时内无显著变化，而与蛋白的结合在4小时时达到最大值，48小时时显著下降。当每隔24小时给予两剂和三剂TCP时，TCP相关放射性与肝蛋白和DNA的结合显示为累积性。用苯巴比妥预处理动物会导致[¹⁴C]TCP当量与蛋白和DNA的共价结合减少，而用SKF 525 - A预处理会导致增加。用β - 萘黄酮预处理大鼠不会改变[¹⁴C]TCP当量与蛋白或DNA的共价结合。然而，用L - 丁硫氨酸 -（R，S）- 亚砜亚胺耗尽谷胱甘肽（GSH）会使与蛋白的结合增加342%，同时使与DNA的结合减少56%。腹腔注射TCP在30和100 mg/kg剂量后2小时也会使肝GSH分别减少41%和61%。体内结合数据表明GSH在TCP的生物活化中具有双重作用。部分原因可能是GSH参与了TCP与肝DNA的生物活化和共价结合。然而，它似乎也能使与蛋白结合的反应性中间体解毒。
