Chamberlain M P, Lock E A, Gaskell B A, Reed C J
School of Biomolecular Sciences, Liverpool John Moores University, UK.
Arch Toxicol. 1998 Jun;72(7):420-8. doi: 10.1007/s002040050522.
The aim of this study was to investigate the role of metabolic activation in the olfactory toxicity of methyl iodide (MeI). Adult male rats were exposed via nose-only inhalation to 100 ppm MeI for 0-6 h, and non-protein sulphydryl (NP-SH) concentrations determined in selected tissues. Depletion of NP-SH occurred in all tissues, but was most marked and rapid in the respiratory epithelium of the nasal cavity and the kidney. Olfactory, lung and liver NP-SH levels were affected to a lesser extent, and those of the brain declined by only 20-30% over the whole time course. In order to modulate glutathione (GSH) status, animals were pre-treated with (1) phorone plus L-buthionine sulphoximine (BSO), which depleted NP-SH levels in all the tissues examined, or (2) the isopropyl ester of GSH (IP-GSH), which was shown to replenish NP-SH concentrations in all tissues except the liver of animals previously administered phorone. When animals were pre-treated with phorone plus BSO and then exposed to 100 ppm MeI for 2 h, there was a potentiation of the toxicity of MeI as judged by the clinical observations on the animals. In contrast, treatment with IP-GSH prior to and during exposure to MeI for 4 h afforded a marked protection to the olfactory epithelium. In order to inhibit cytochromes P450, animals were pre-treated with cobalt protoporphyrin IX. This decreased hepatic cytochrome P450 concentrations by > 90%, but when animals were then exposed to 100 ppm MeI for 4 h there was no effect on the severity of the olfactory lesion. These results indicate that conjugation of MeI with GSH is a detoxification rather than an activation pathway. Also, there is no major role for cytochrome P450-dependent oxidation in the development of the olfactory lesion.
本研究的目的是调查代谢活化在甲基碘（MeI）嗅觉毒性中的作用。成年雄性大鼠通过仅经鼻吸入100 ppm的MeI，暴露0至6小时，并测定选定组织中的非蛋白质巯基（NP-SH）浓度。所有组织中NP-SH均有消耗，但在鼻腔呼吸上皮和肾脏中最为明显且迅速。嗅觉、肺和肝脏的NP-SH水平受到的影响较小，而大脑中的NP-SH水平在整个时间过程中仅下降了20%至30%。为了调节谷胱甘肽（GSH）状态，动物预先接受以下处理：（1）佛尔酮加L-丁硫氨酸亚砜胺（BSO），其使所有检测组织中的NP-SH水平降低；或（2）GSH异丙酯（IP-GSH），已证明其可补充除先前给予佛尔酮的动物肝脏外所有组织中的NP-SH浓度。当动物预先用佛尔酮加BSO处理，然后暴露于100 ppm的MeI中2小时时，根据对动物的临床观察判断，MeI的毒性增强。相反，在暴露于MeI之前及期间用IP-GSH处理4小时，可对嗅觉上皮提供显著保护。为了抑制细胞色素P450，动物预先用原卟啉钴IX处理。这使肝脏细胞色素P450浓度降低>90%，但当动物随后暴露于100 ppm的MeI中4小时时，对嗅觉损伤的严重程度没有影响。这些结果表明，MeI与GSH的结合是一条解毒途径而非活化途径。此外，细胞色素P450依赖性氧化在嗅觉损伤的发生中没有主要作用。
