Glutathione conjugation and cytochrome P-450 metabolism of methyl chloride in vitro

Abstract

Possible carcinogenic properties of methyl chloride (CH 3Cl) have been under discussion since an increase of renal tumours was observed in male B6C3F 1 mice after a 2-yr inhalation exposure to the substance. This was, however, only observed following exposure of male mice to the highest concentration level and not after exposure of females or F344 rats of both sexes. Accumulation of formaldehyde in the kidneys was thought to be responsible for tumour production. In the experiments presented here, cytosolic enzymes from the liver and kidneys of different mouse strains and F344 rats were incubated in head-space vials with methyl chloride or methyl bromide. Following equilibration, the decrease in the concentration of the gases was monitored by gas chromatography as a parameter for metabolic elimination. The metabolic turnover of the methyl halides was found to be significantly higher in female animals than in the males. In parallel experiments, the glutathione content of the liver and kidneys of mice exposed by inhalation to 1000 ppm methyl chloride was determined. In both organs, the glutathione content diminished rapidly after exposure to the methyl halide. The glutathione depletion was slightly greater in females than in males. Finally, the content of cytochromes P-450, P-420 and b5 was determined in liver and kidneys of different mouse strains by difference spectroscopy. Female mice were found to have a lower content of P-450 and b5 than males in the kidneys; there was no such sex difference in liver tissue. The results show that a sex difference in metabolism is unlikely to be responsible for the unique kidney tumour production in male B6C3F 1 mice. Other possible explanations are discussed.