FORMATION AND REACTIVITY OF ALTERNATIVE QUINONE METHIDES FROM BUTYLATED HYDROXYTOLUENE - POSSIBLE EXPLANATION FOR SPECIES-SPECIFIC PNEUMOTOXICITY
FORMATION AND REACTIVITY OF ALTERNATIVE QUINONE METHIDES FROM BUTYLATED HYDROXYTOLUENE - POSSIBLE EXPLANATION FOR SPECIES-SPECIFIC PNEUMOTOXICITY
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DOI：
10.1021/tx00013a011
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发表时间：
1990-01-01
影响因子：
4.1
通讯作者：
THOMPSON, JA
中科院分区：
文献类型：
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作者：
BOLTON, JL;SEVESTRE, H;THOMPSON, JA
先前的工作已经表明，丁基化羟基甲苯[2，6-二叔丁基-4-甲基苯酚（BHT）]经历π-在肝微粒体中氧化形成醌甲基化物2，6-二叔丁基-4-亚甲基-2，5-环己二烯酮（QM）。这种亲电子物质与谷胱甘肽和蛋白硫醇共价结合，据信可引发小鼠肺毒性。在本研究中，我们鉴别了BHT的另一种醌甲基化物代谢产物6-叔丁基-2-（羟基-叔丁基）-4-亚甲基-2，5-环己二烯酮（QM-OH），其在BHT的微粒体叔丁基羟基化后形成。小鼠肝和肺微粒体产生两种醌甲基化物，并且获得了两种代谢物也在体内形成的证据。相比之下，大鼠微粒体几乎只产生QM，只有痕量的QM-OH在肝脏中形成，而在肺中没有。两种醌甲基化物与GSH的化学反应性的研究表明，QM-OH的反应速度比QM快约6倍。红外光谱、1H NMR光谱和电化学测量都支持QM-OH的亲电性增强是由于环氧与侧链羟基的分子内氢键作用。因此，结果提供了证据，即先前用于将BHT生物活化为肺毒素的代谢方案应被修改以包括叔丁基羟基化和随后的π-氧化成活化的亲电试剂QM-OH。该方案与有关BHT诱导肺毒性的已发表数据一致，并解释了该效应的种属特异性。
Previous work has shown that butylated hydroxytoluene [2,6-di-tert-butyl-4-methylphenol (BHT)] undergoes .pi.-oxidation in liver microsomes to form the quinone methide 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone (QM). This electrophilic species binds covalently to glutathione and protein thiols and is believed to initiate pulmonary toxicity in mice. In the present investigation, we identified another quinone methide metabolite of BHT, 6-tert-butyl-2-(hydroxy-tert-butyl)-4-methylene-2,5-cyclohexadienone (QM-OH), formed subsequent to the microsomal hydroxylation of BHT at a tert-butyl group. Mouse liver and lung microsomes generate the two quinone methides, and evidence was obtained that both metabolites also are formed in vivo. In contrast, rat microsomes produce QM almost exclusively, with only traces of QM-OH formed in liver and none in lung. Studies of the chemical reactivities of the two quinone methides with GSH demonstrated that QM-OH reacts about 6-fold faster than QM. Infrared spectra, 1H NMR spectra, and electrochemical measurements all support the proposal that the enhanced electrophilicity of QM-OH is due to intramolecular hydrogen bonding of the ring oxygen with the side-chain hydroxyl. The results provide evidence, therefore, that the previous metabolic scheme for bioactivation of BHT to a pulmonary toxin should be amended to include tert-butyl hydroxylation and subsequent .pi.-oxidation to the activated electrophile QM-OH. This scheme is consistent with published data concerning BHT-induced pulmonary toxicity and provides as explanation for the species specificity of this effect.