Vinylidene chloride: changes in drug-metabolizing enzymes, mutagenicity and relation to its targets for carcinogenesis.

Abstract

Results of various studies have shown that male Swiss Webster mice are more susceptible to toxic effects of vinylidene chloride (VDC) than are females of the same mouse strain, females and males of the C57BL mouse strain, Chinese hamsters and rats. The main targets of toxicity are kidney and liver. The kidney of male Swiss Webster mice is the only organ where VDC unambiguously induces tumours. In the present study we have investigated the ability of NADPH-foritifed postmitochondrial supernatant fractions (S-9 mix) of kidney and liver from susceptible and nonsusceptible animals to activate VDC to a bacterial mutagen. The following sequence of activating potencies was observed: mouse liver (both strains and sexes) and Chinese hamster liver greater than rat liver greater than human liver greater than Chinese hamster kidney greater than kidney from male mice of both strains greater than kidney from rats and female mice. The last two preparations only occasionally showed weak activation of VDC. Addition of purified microsomal epoxide hydrolase to S-9 mix did not affect the mutagenicity of VDC; addition of glutathione reduced the mutagenicity up to 50%. Pretreatment of animals (male rats, male and female Swiss Webster mice) with VDC did not potentiate the ability of the subcellular preparations to activate this compound. In fact, in some cases, a weaker activation was observed. Following this treatment, microsomal 7-ethoxy-coumarin O-dealkylase was decreased in mouse kidney and in rat liver. The enzyme was not affected in mouse liver and was not measurable in rat kidney. Microsomal epoxide hydrolase activity (with styrene 7,8-oxide as substrate) was not affected in mouse liver and rat kidney. In the kidney of male mice treated with a high concentration of VDC, epoxide hydrolase activity was decreased initially, but after longer treatment, in some cases a weak increase above control was noticed. A stronger increase in activity of epoxide hydrolase was observed in the rat liver and the kidney of female mice. Cytosolic glutathione transferase activity (with 2,4-dinitrochlorobenzene as substrate) was not affected by the VDC treatment in the liver of male mice, but was decreased in the kidney of male mice, and was elevated in the kidney and liver of rats and of female mice. The different effects of VDC on this enzyme may be one of the reasons for the differences in susceptibility towards the toxic and carcinogenic actions of this compound in different species, strains and sexes.