Snyderwine E G, Kroll R, Rubin R J
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205.
Toxicol Appl Pharmacol. 1988 Mar 30;93(1):11-21. doi: 10.1016/0041-008x(88)90021-x.
Acute treatment with ethanol and other alcohols has been shown to potentiate the hepatotoxicity of certain xenobiotics, in part via induction of the mixed-function oxidase (MFO) system. Carbon disulfide (CS2)-induced hepatotoxicity and inhibition of the MFO system have been shown to be a consequence of MFO metabolism. In the present study, the ability of several different alcohols to induce the hepatic MFO metabolism of CS2 and the effects of this induction on CS2 distribution and hepatotoxicity were examined in rats. Eighteen hours after alcohol administration (1/2 LD50 dose, po), CS2 microsomal MFO metabolism was significantly enhanced, in order of descending potency, by isopropanol, methanol, and ethanol pretreatments, but not by isobutanol pretreatment. The degree of enhancement of CS2 metabolism by different alcohols paralleled the enhancement of nitroanisole O-demethylation and aniline hydroxylation, MFO activities associated with the ethanol-inducible isozyme of cytochrome P450. CS2 (1 mg/kg, ip, 3 hr) inhibited only the cytochrome P450-mediated activities enhanced by alcohol pretreatment. These results suggest that CS2 metabolism is catalyzed by the ethanol-inducible isozyme. Alcohol-induced rats had significantly more 14CS2-derived radioactivity in the liver than control and isobutanol-pretreated rats 3 hr after dosing (1 mg/kg, ip). However, only methanol pretreatment resulted in an increased retention of 14CS2-derived radioactivity in plasma, brain, and kidney. Unlike other alcohol pretreatments, methanol decreased the total 14C expired during the 3-hr period after CS2 dosing and caused a significant (twofold) increase in plasma glutamic-pyruvic transaminase, measured 24 hr after CS2 exposure (625 mg/kg). These data indicate that alcohol induction of MFO-dependent CS2 metabolism per se is not sufficient to result in CS2-induced hepatic damage although it does lead to loss of specific cytochrome P450 function.
乙醇和其他醇类的急性处理已被证明会增强某些外源化学物的肝毒性，部分是通过诱导混合功能氧化酶（MFO）系统。二硫化碳（CS2）诱导的肝毒性和对MFO系统的抑制已被证明是MFO代谢的结果。在本研究中，检测了几种不同醇类诱导大鼠肝脏中CS2的MFO代谢的能力以及这种诱导对CS2分布和肝毒性的影响。给予酒精（1/2 LD50剂量，经口）18小时后，异丙醇、甲醇和乙醇预处理按效力递减顺序显著增强了CS2微粒体MFO代谢，但异丁醇预处理未增强。不同醇类对CS2代谢的增强程度与硝基苯甲醚O-去甲基化和苯胺羟基化的增强程度平行，硝基苯甲醚O-去甲基化和苯胺羟基化是与细胞色素P450乙醇诱导同工酶相关的MFO活性。CS2（1 mg/kg，腹腔注射，3小时）仅抑制了酒精预处理增强的细胞色素P450介导的活性。这些结果表明CS2代谢由乙醇诱导同工酶催化。给药（1 mg/kg，腹腔注射）3小时后，酒精诱导的大鼠肝脏中源自14CS2的放射性比对照和异丁醇预处理的大鼠显著更多。然而，只有甲醇预处理导致血浆、脑和肾中源自14CS2的放射性保留增加。与其他酒精预处理不同，甲醇减少了CS2给药后3小时内呼出的总14C，并导致在CS2暴露（625 mg/kg）后24小时测量的血浆谷丙转氨酶显著（两倍）升高。这些数据表明，酒精诱导的依赖MFO的CS2代谢本身不足以导致CS2诱导的肝损伤，尽管它确实导致特定细胞色素P450功能丧失。
