Production of Formaldehyde during Metabolism of Dimethyl Sulfoxide by Hydroxyl Radical Generating Systems

Dimethyl sulfoxide is a potent hydroxyl radical scavenging agent. The production of methane from dimethyl sulfoxide has been used to detect the generation of hydroxyl radicals in biological systems. In the current report, evidence is presented that formaldehyde is produced during the interaction of dimethyl sulfoxide with hydroxyl radicals. Formaldehyde, rather than methane, represents a major product of this interaction. Three model hydroxyl radical generating systems were used in this investigation. They were (1) the oxidation of xanthine by xanthine oxidase, (2) the iron-catalyzed oxidation of ascorbic acid, and (3) NADPH-dependent electron transfer by rat liver microsomes. Formaldehyde was produced from dimethyl sulfoxide in a time-dependent manner by all three systems. Formaldehyde production was inhibited by competing hydroxyl radical scavenging agents such as benzoate, mannitol, and 2-keto-4-thiomethylbutyric acid. Catalase completely inhibited the production of formaldehyde in the xanthine oxidase and the ascorbate systems. Azide, an inhibitor of catalase (present as a contaminant in isolated microsomes), stimulated the production of formaldehyde during microsomal electron transfer. These results indicate that H₂O₂ serves as a precursor of hydroxyl radicals in the three systems. Superoxide dismutase inhibited formaldehyde production by the xanthine oxidase system but not by the ascorbate system. Diethylenetriaminepentaacetic acid iiihibited the production of formaldehyde by the xanthine oxidase system to a mubh greater extent than it did in the ascorbate system. The addition of iron-EDTA stimulated formaldehyde production. It is suggested that hydroxyl radicals are generated by the xanthine oxidase system and by the ascorbate system via a Fenton reaction in which the reduction of iron is brought about either by superoxide radical or by ascorbate. Considerably greater amounts of formaldehyde than of metháne were produced by all three hydroxyl radical generating systems. The production of formaldehyde from dimethyl sulfoxide may represent a corlvenient technique to detect and to evaluate the role of hydroxyl radicals in some biological systems. In view of the production of formaldehyde, dimethyl sulfoxide should not be considered to be an inert solvent in biological systems. The possibility that formaldehyde is a metabolite of the in vivo metabolism of dimethyl sulfoxide remains to be evaluated.