Studies on the mechanism of enhancement of butylated hydroxytoluene-induced mouse lung toxicity by butylated hydroxyanisole.
Studies on the mechanism of enhancement of butylated hydroxytoluene-induced mouse lung toxicity by butylated hydroxyanisole.
复制标题
DOI：
10.1016/0041-008x(88)90254-2
复制
发表时间：
1988-10
影响因子：
3.8
通讯作者：
D. Thompson;M. Trush
中科院分区：
文献类型：
--
作者：
D. Thompson;M. Trush
本报告中描述的研究旨在探索丁基羟基茴香醚（BHA）能够增强丁基羟基甲苯（BHT）诱导的小鼠肺毒性的可能机制。在小鼠肺切片实验中，BHA增强了BHT与蛋白质的共价结合，表明BHA和BHT之间的相互作用发生在肺中。雄性CD-1小鼠皮下给予BHA（250 mg/kg）或马来酸二乙酯（DEM，1 ml/kg），均产生了类似的BHT诱导肺毒性增强。与DEM相反，BHA（250或1500 mg/kg）给药未降低小鼠肺谷胱甘肽水平，表明BHA的作用不是由于谷胱甘肽水平的消耗。我们之前观察到，在存在模型过氧化物酶的情况下，BHA和BHT之间发生独特的相互作用，导致BHT的代谢活化增加。向小鼠肺微粒体中加入过氧化氢或各种氢过氧化物后。BHA显著增加BHT与蛋白质的共价结合。BHA还刺激了小鼠肺微粒体中过氧化氢的形成速率，增加了4.7倍。同样地，由NADPH细胞色素P-450（c）还原酶催化叔丁基对苯二酚（BHA的微粒体代谢物）的氧化还原循环产生的过氧化氢支持过氧化物酶依赖性BHA增强BHT-醌甲基化物的形成。这些结果表明，由于过氧化氢的形成增加以及随后因BHA与BHT的直接相互作用而产生的过氧化物酶依赖性的BHT-醌甲基化物的形成，因此BHA可以促进肺部中BHT的活化。
The studies described in this report were designed to probe possible mechanisms whereby butylated hydroxyanisole (BHA) is able to enhance butylated hydroxytoluene (BHT)-induced mouse lung toxicity. In experiments with mouse lung slices, BHA enhanced the covalent binding of BHT to protein, indicating that the interaction between BHA and BHT takes place in the lung. Subcutaneous administration of either BHA (250 mg/kg) or diethyl maleate (DEM, 1 ml/kg) to male CD-1 mice produced a similar enhancement of BHT-induced lung toxicity. In contrast to DEM, the administration of BHA (250 or 1500 mg/kg) did not decrease mouse lung glutathione levels, suggesting that the effect of BHA is not due to the depletion of glutathione levels. We previously observed that in the presence of model peroxidases a unique interaction occurs between BHA and BHT, resulting in the increased metabolic activation of BHT. Upon the addition of hydrogen peroxide or various hydroperoxides to mouse lung microsomes. BHA significantly increased the covalent binding of BHT to protein. BHA also stimulated the rate of formation of hydrogen peroxide by 4.7-fold in mouse lung microsomes. Likewise, hydrogen peroxide resulting from the NADPH cytochrome P-450 (c) reductase-catalyzed redox cycling of tert-butylhydroquinone, a microsomal metabolite of BHA, supported the peroxidase-dependent BHA-enhanced formation of BHT-quinone methide. These results suggest that BHA could facilitate the activation of BHT in the lung as a result of both the increased formation of hydrogen peroxide and the subsequent peroxidase-dependent formation of BHT-quinone methide from the direct interaction of BHA with BHT.