Smith A C, Roberts S M, Berman L M, Harbison R D, James R C
Battelle Columbus Laboratories, Toxicology Program Office, McLean, VA.
Toxicology. 1988 Jun;50(1):95-105. doi: 10.1016/0300-483x(88)90124-2.
A series of experiments were conducted to examine the potential role of phase I metabolism in halothane-induced liver injury in the hyperthyroid rat. The metabolism of halothane was determined in both hyperthyroid (triiodothyronine, 3 mg/kg per day, for 6 days) and euthyroid rats and in animals pre-treated with the cytochrome P-450 inhibitor piperonyl butoxide (75-100 mg/kg, i.p.). It was found that the hyperthyroid state, which is associated with a substantial increase in sensitivity to the hepatotoxic effects of halothane, decreases both oxidative and reductive routes of halothane metabolism in the rat. The production of trifluoroacetic acid (TFA), an oxidative metabolite, as well as that of chlorodifluoroethylene (CDF) and chlorotrifluoroethane (CTF), 2 reductive metabolites, was significantly reduced in hyperthyroid animals. Consistent with these findings serum and urinary bromide levels resulting from the formation of TFA, CDF or CTF were significantly reduced. The only route of halothane metabolism significantly increased by the hyperthyroid condition was the defluorination of halothane. Piperonyl butoxide administration did not render euthyroid animals sensitive to the halothane-induced hepatotoxicity and had no effect on the defluorination of halothane in euthyroid animals. However, piperonyl butoxide markedly increased the hepatotoxicity of halothane in hyperthyroid rats and, except for a modest increase in debromination reactions, decreased all measured indices of halothane metabolism including the defluorination of halothane. Thus, none of the observed changes in halothane metabolism produced by triiodothyronine or piperonyl butoxide treatment could be consistently correlated to the increases in hepatotoxicity linked to these 2 treatments. Based on these studies we suggest that the halothane hepatotoxicity induced in the hyperthyroid rat results from effects produced by either the parent compound or an as yet unidentified metabolite. In addition, these studies further demonstrate that considerable mechanistic differences exist for halothane-induced hepatotoxicity when comparing euthyroid and hyperthyroid animal models.
进行了一系列实验，以研究I相代谢在甲状腺功能亢进大鼠氟烷性肝损伤中的潜在作用。测定了甲状腺功能亢进（每天3mg/kg三碘甲状腺原氨酸，共6天）和甲状腺功能正常大鼠以及用细胞色素P-450抑制剂胡椒基丁醚（75-100mg/kg，腹腔注射）预处理的动物中氟烷的代谢情况。结果发现，甲状腺功能亢进状态与对氟烷肝毒性作用的敏感性显著增加有关，它降低了大鼠体内氟烷代谢的氧化和还原途径。在甲状腺功能亢进的动物中，氧化代谢产物三氟乙酸（TFA）以及两种还原代谢产物二氟氯乙烯（CDF）和三氟氯乙烷（CTF）的生成均显著减少。与这些发现一致的是，由TFA、CDF或CTF形成导致的血清和尿溴水平显著降低。甲状腺功能亢进状态唯一显著增加的氟烷代谢途径是氟烷的脱氟作用。给予胡椒基丁醚并未使甲状腺功能正常的动物对氟烷诱导的肝毒性敏感，且对甲状腺功能正常动物的氟烷脱氟作用没有影响。然而，胡椒基丁醚显著增加了甲状腺功能亢进大鼠中氟烷的肝毒性，并且除了脱溴反应略有增加外，降低了所有测定的氟烷代谢指标，包括氟烷的脱氟作用。因此，三碘甲状腺原氨酸或胡椒基丁醚处理所导致的氟烷代谢的任何观察到的变化，均无法与这两种处理相关的肝毒性增加始终如一地关联起来。基于这些研究，我们认为甲状腺功能亢进大鼠中诱导的氟烷肝毒性是由母体化合物或尚未鉴定的代谢产物产生的效应所致。此外，这些研究进一步证明，在比较甲状腺功能正常和甲状腺功能亢进动物模型时，氟烷诱导的肝毒性存在相当大的机制差异。
