Bioactivation of [13C]dichloromethane in mouse, rat, and human liver cytosol: 13C nuclear magnetic resonance spectroscopic studies.
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.
Hashmi
M
M
Department of Pharmacology, University of Rochester, New York 14642.
Dechert
S
S
Dekant
W
W
Anders
M W
MW
D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism*; D005557:Formaldehyde / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008752:Methylene Chloride / Q000493:pharmacokinetics*; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011916:Rats, Inbred F344
D005557:Formaldehyde; D008752:Methylene Chloride; D005978:Glutathione