Chamberlain M P, Lock E A, Reed C J
School of Biomolecular Sciences, Liverpool John Moores University, UK.
Toxicology. 1998 Aug 21;129(2-3):169-81. doi: 10.1016/s0300-483x(98)00084-5.
The monohalomethane methyl iodide (MeI) is a site specific toxin within the nasal cavity of the rat, selectively damaging the olfactory epithelium (OE) whilst respiratory epithelium (RE) is spared. The aim of this study was to investigate the rates and routes of metabolism of MeI within the nasal cavity, in order to understand the reasons for the observed site-selectivity. Cytosolic glutathione S-transferases (GSTs) of both OE and RE catalysed the conjugation of MeI with glutathione (GSH), but rates were 4-fold higher in OE than RE. The product of this reaction was confirmed as S-methyl GSH. In both OE and liver the GST catalysing the conjugation of MeI was shown to belong to the theta class. No cytochrome P450-dependent oxidation of MeI to formaldehyde could be detected in incubations containing hepatic or olfactory microsomes. Intact nasal turbinates were incubated with [14C]-MeI, and a dose- and time-dependent covalent binding of MeI to olfactory protein was demonstrated. The rates of protein methylation were found to be similar in OE and RE. Thus the only parameter that correlates with the site-selectivity of the observed lesion is the rate of conjugation of MeI with GSH. Whether toxicity is due to production of a reactive metabolite or GSH depletion per se, remains to be elucidated.
一卤代甲烷甲基碘（MeI）是大鼠鼻腔内的一种位点特异性毒素，它能选择性地损伤嗅上皮（OE），而呼吸上皮（RE）则不受影响。本研究的目的是调查MeI在鼻腔内的代谢速率和途径，以了解观察到的位点选择性的原因。OE和RE的胞质谷胱甘肽S-转移酶（GSTs）都能催化MeI与谷胱甘肽（GSH）的结合，但OE中的反应速率比RE高4倍。该反应的产物被确认为S-甲基谷胱甘肽。在OE和肝脏中，催化MeI结合的GST都属于θ类。在含有肝脏或嗅微粒体的孵育体系中，未检测到细胞色素P450依赖性的MeI氧化为甲醛的反应。完整的鼻甲与[14C]-MeI一起孵育，结果表明MeI与嗅蛋白的共价结合具有剂量和时间依赖性。发现OE和RE中蛋白质甲基化的速率相似。因此，与观察到的损伤位点选择性相关的唯一参数是MeI与GSH结合的速率。毒性是由于产生了反应性代谢产物还是GSH本身的消耗，仍有待阐明。
