Levamisole inhibition of microsomal lipid peroxidation as related to its sulfhydryl metabolite dl-2-oxo-3-(2-mercaptoethyl)-5-phenylimadazolidine.

Levamisole was previously shown to protect rat liver microsomes from lipid peroxidation induced by ADP-Fe and either NADPH, ascorbate, or X irradiation. The present experiments provide information about the mechanism of protection. Incubation of levamisole with a microsomal system containing ADP-Fe and NADPH resulted in protection of sulfhydryl groups, whereas reaction of levamisole with ascorbate (nonenzymatic system) indicated generation of a sulfhydryl metabolite. Production of a sulfhydryl metabolite of levamisole, dl-2-oxo-3-(2-mercaptoethyl)-5-phenylimidazolidine (OMPI), in either the enzymatic or nonenzymatic system was demonstrated by gas chromatography-mass spectrometry. While levamisole acts as an antioxidant at concentrations of 1.0 and 2.0 mM, OMPI had an enigmatic effect on microsomal lipid peroxidation induced enzymatically or nonenzymatically. OMPI exhibited a biphasic effect: at concentrations below 25 microM a prooxidant effect was observed, and at concentrations exceeding 50 microM an antioxidant effect was observed. The data suggest that the inhibition of microsomal lipid peroxidation by levamisole is due to the generation of a sulfhydryl metabolite and that the active intermediate is probably OMPI.