Thompson D C, Trush M A
Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland 21205.
Toxicol Appl Pharmacol. 1988 Oct;96(1):122-31. doi: 10.1016/0041-008x(88)90254-2.
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.
本报告中描述的研究旨在探究丁基化羟基茴香醚（BHA）能够增强丁基化羟基甲苯（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与BHT之间的相互作用发生在肺中。给雄性CD-1小鼠皮下注射BHA（250 mg/kg）或马来酸二乙酯（DEM，1 ml/kg）均可产生类似的BHT诱导的肺毒性增强作用。与DEM不同，BHA（250或1500 mg/kg）的给药并未降低小鼠肺中的谷胱甘肽水平，这表明BHA的作用并非由于谷胱甘肽水平的耗竭。我们之前观察到，在模型过氧化物酶存在的情况下，BHA与BHT之间会发生独特的相互作用，从而导致BHT的代谢活化增加。向小鼠肺微粒体中添加过氧化氢或各种氢过氧化物后，BHA显著增加了BHT与蛋白质的共价结合。BHA还使小鼠肺微粒体中过氧化氢的生成速率提高了4.7倍。同样，由BHA的微粒体代谢产物叔丁基对苯二酚的NADPH细胞色素P-450（c）还原酶催化的氧化还原循环产生的过氧化氢，支持了过氧化物酶依赖性BHA增强的BHT-醌甲基化物的形成。这些结果表明，由于过氧化氢生成增加以及随后BHA与BHT直接相互作用导致的过氧化物酶依赖性BHT-醌甲基化物的形成，BHA可能促进了肺中BHT的活化。
