EFFECT OF PRETREATMENT WITH DICHLOROACETATE OR TRICHLOROACETATE ON THE METABOLISM OF BROMODICHLOROACETATE

Abstract

Haloacetates are a common class of water chlorination by-products. Depending on the amount of bromide in the source water, varying amounts of chlorinated, brominated, and mixed bromochloro haloacetates are produced. When administered to rodents, halo acetates have been shown to increase formation of thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine levels in the liver. These responses appear to be modified by prior treatment. To examine potential mechanisms that account for these modifications in oxidative stress, the ability of trichloroacetate (TCA) or dichloroacetate (DCA) pretreat-ment to alter the metabolism of bromodichloroacetate (BDCA) and the disposition of its metabolites was examined in male B6C3F1 mice. Two-week pretreatment with I g/L DCA and TCA in the drinking water of mice alters the initial hepatic metabolism of BDCA and the further metabolism of its metabolite DCA. DCA pretreatment inhibits cytosolic metabo lism of both I raM DCA or BDCA up to 70%. In contrast, DCA pretreatment stimulates hepatic microsomal BDCA metabolism 1.3-fold but has little effect on microsomal metabo lism of DCA. Increased microsomal metabolism of BDCA appears to be attributable to the induction of a metabolic pathway that produces CO₂ and bromodichloromethane (BDCM) as metabolites. TCA pretreatment inhibits BDCA metabolism up to 70% in the cytosol and 30% in microsomes but has little effect on DCA metabolism. These results indicate that the hepatic metabolism of the haloacetates becomes quite complex at the high doses that have been employed in cancer bioassays. BDCA serves as a good exam ple, because it is metabolized to at least two carcinogenic metabolites that have different modes of action, BDCM and DCA. As doses approach those that induce cancer in mice, the proportion of and amounts of these metabolites as a fraction of the dose administered will change substantially. This article demonstrates that those interactions will occur from mixed treatment with haloacetates as well.

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Notes on contributors

Eric W. Austin

Current address for Eric W. Austin is AMUR Research Corp., 1815 Old County Rd., Belmont, CA 94002, USA.

R. J. Bull

Address correspondence to Richard J. Bull, Molecular Biosciences, Battelle Pacific Northwest National Laboratories, P.O. Box 999-P7-56, Richland, WA 99352, USA.