title: Limited reactivity of formyl chloride with glutathione and relevance to metabolism and toxicity of dichloromethane.
abstract: Formyl chloride has been indirectly implicated as an intermediate in the oxidation of CH(2)Cl(2) and proposed to be a product of the oxidation of some other compounds. Formyl chloride was synthesized and added to aqueous solutions, with CO formed as a product. The presence of glutathione (GSH) did not reduce the yield of CO at any of the pH values tested. At pH >or= 9, a small amount of S-formyl GSH was detected (<or =3% of CO formed) and identified by comparison with synthetic material using mass spectrometry. Incubations of CH(2)Cl(2) with human liver microsomes at neutral pH produced mainly CO and only trace protein adducts (detected from (14)CH(2)Cl(2)) and no S-formyl GSH at the level of detection. Neither rat liver cytosol nor purified GSH transferase (rat) 5-5 or (human) T1-1 significantly enhanced the level of S-formyl GSH recovered in incubations with either NADPH-fortified microsomes and CH(2)Cl(2) or synthetic formyl chloride. The oxidation pathway is the principal route of metabolism of CH(2)Cl(2) at low doses in vivo, and previous literature assumes that the formyl chloride product is reactive with GSH and protein. We provide evidence that formyl chloride can react with GSH but that, in contrast to suggestions in the literature, the extent is very limited because of the known high rate of rearrangement to CO in aqueous solution. The very limited reaction of formyl chloride with nucleophiles is consistent with the low toxicity of CH(2)Cl(2), and formyl chloride binding cannot be used as an explanation for discrepancies in pharmacokinetic models [Gargas, M. L., Clewell, H. J., III, and Andersen, M. E. (1986) Toxicol. Appl. Pharmacol. 82, 211-223; Clewell, H. J., III (1995) Toxicology 102, 83-94].
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
authors.forename: Kengo
authors.initials: K
authors.lastname: Watanabe
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D005561:Formates / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008752:Methylene Chloride / Q000378:metabolism* / Q000633:toxicity*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005561:Formates; D008752:Methylene Chloride; D005978:Glutathione