Hashmi M, Dechert S, Dekant W, Anders M W
Department of Pharmacology, University of Rochester, New York 14642.
Chem Res Toxicol. 1994 May-Jun;7(3):291-6. doi: 10.1021/tx00039a004.
Dichloromethane is tumorigenic in lungs and liver of B6C3F1 mice, but is not tumorigenic in rats or hamsters, and its toxicity is associated with glutathione-dependent bioactivation. The objective of the present studies was to investigate the glutathione-dependent bioactivation of [13C]dichloromethane in mouse, rat, and human liver cytosol and the fate of dichloromethane-derived reactive intermediates with 13C NMR. [13C]Formaldehyde hydrate, [13C]S-(hydroxymethyl)glutathione, and [13C]methanol were identified as metabolites of [13C]dichloromethane. [13C]S-(Chloromethyl)glutathione, a putative intermediate in the glutathione-dependent bioactivation of dichloromethane, or derived adducts were not observed. Moreover, no evidence for the formation of S,S'-methylenebis[glutathione] by reaction of glutathione and formaldehyde under physiological conditions was obtained, although methanol was observed as a product. S,S'-Methylenebis[glutathione] was, however, formed by reaction of glutathione and formaldehyde at pH 1. S-(Chloromethyl)-N-acetyl-L-cysteine methyl ester, a surrogate for S-(chloromethyl)glutathione, was prone to hydrolysis. These results corroborate the finding that formaldehyde is a reactive intermediate formed during the glutathione-dependent bioactivation of dichloromethane that may be involved in the observed tumorigenicity of dichloromethane in susceptible species. The results also indicate that S-(chloromethyl)glutathione is an intermediate in the glutathione-dependent bioactivation of dichloromethane and may also play a role in its mutagenicity and carcinogenicity.
二氯甲烷对B6C3F1小鼠的肺和肝脏具有致癌性，但对大鼠或仓鼠无致癌性，其毒性与谷胱甘肽依赖性生物活化有关。本研究的目的是利用13C核磁共振研究[13C]二氯甲烷在小鼠、大鼠和人肝细胞溶胶中的谷胱甘肽依赖性生物活化以及二氯甲烷衍生的反应性中间体的归宿。[13C]水合甲醛、[13C]S-(羟甲基)谷胱甘肽和[13C]甲醇被鉴定为[13C]二氯甲烷的代谢产物。未观察到[13C]S-(氯甲基)谷胱甘肽，即二氯甲烷谷胱甘肽依赖性生物活化中的假定中间体或衍生加合物。此外，尽管观察到甲醇是产物，但在生理条件下未获得谷胱甘肽与甲醛反应形成S,S'-亚甲基双[谷胱甘肽]的证据。然而，谷胱甘肽与甲醛在pH 1条件下反应形成了S,S'-亚甲基双[谷胱甘肽]。S-(氯甲基)-N-乙酰-L-半胱氨酸甲酯作为S-(氯甲基)谷胱甘肽的替代物，易于水解。这些结果证实了甲醛是二氯甲烷谷胱甘肽依赖性生物活化过程中形成的反应性中间体这一发现，该中间体可能与二氯甲烷在易感物种中观察到的致癌性有关。结果还表明，S-(氯甲基)谷胱甘肽是二氯甲烷谷胱甘肽依赖性生物活化的中间体，也可能在其致突变性和致癌性中起作用。
