Mizutani T, Yamamoto K, Tajima K
Toxicol Appl Pharmacol. 1983 Jun 30;69(2):283-90. doi: 10.1016/0041-008x(83)90310-1.
A comparative test in mice for pulmonary toxicity between butylated hydroxytoluene (2,6-di-tert.-butyl-4-methylphenol, BHT) and 2,6-di-tert.-butyl-4-[alpha, alpha, alpha-2H3]methylphenol (BHT-d3) showed a significantly lower toxic potency of the latter. The rate of in vitro BHT metabolism to 2,6-di-tert.-butyl-4-methylene-2,5-cyclohexadienone (BHT-QM) was slowed by deuterating BHT in the 4-methyl group. On the other hand, the rate of in vitro metabolism to 2,6-di-tert.-butyl-4-hydroxy-4-methyl-2,5-cyclohexadienone (BHT-OH) was increased with the deuteration. A similar isotope effect of the deuterium substitution on the in vivo metabolic rates of BHT was observed. These observations support the concept that the lung damage caused by BHT is mediated by BHT-QM. The pulmonary toxicity of 2-tert.-butyl-4-ethylphenol (4-EP) and their deuterated analogs was also compared. 2-tert.-Butyl-4-[1,1-2H2]ethylphenol (4-EP-d2) showed a significantly lower toxic potency than 4-EP, whereas 2-tert.-butyl-4-[2,2,2-2H3]ethylphenol (4-EP-d3) showed a toxic potency comparable to that of 4-EP. This result is consistent with the hypothesis that a quinone methide metabolite is responsible for the onset of lung damage produced by 4-EP as well as BHT.
对小鼠进行的关于丁基化羟基甲苯（2,6 - 二叔丁基 - 4 - 甲基苯酚，BHT）和2,6 - 二叔丁基 - 4 - [α,α,α - 2H₃]甲基苯酚（BHT - d₃）肺部毒性的比较试验表明，后者的毒性效力显著较低。通过在4 - 甲基上氘代BHT，BHT体外代谢为2,6 - 二叔丁基 - 4 - 亚甲基 - 2,5 - 环己二烯酮（BHT - QM）的速率减慢。另一方面，随着氘代，体外代谢为2,6 - 二叔丁基 - 4 - 羟基 - 4 - 甲基 - 2,5 - 环己二烯酮（BHT - OH）的速率增加。观察到氘取代对BHT体内代谢速率有类似的同位素效应。这些观察结果支持了BHT引起的肺损伤是由BHT - QM介导的这一概念。还比较了2 - 叔丁基 - 4 - 乙基苯酚（4 - EP）及其氘代类似物的肺部毒性。2 - 叔丁基 - 4 - [1,1 - 2H₂]乙基苯酚（4 - EP - d₂）的毒性效力明显低于4 - EP，而2 - 叔丁基 - 4 - [2,2,2 - 2H₃]乙基苯酚（4 - EP - d₃）的毒性效力与4 - EP相当。这一结果与醌甲基化物代谢物导致4 - EP以及BHT引起的肺损伤这一假设一致。
