The relevance of covalent binding to mouse liver DNA to the carcinogenic action of hexachlorocyclohexane isomers

Abstract

mutational processes must be more important for the carcinogenicity of HCH. IntroductionHexachlorocyclohexane (HCH)* comprises of a group of isomers of which the gamma-isomer, later called lindane, has very useful pesticidal activity (1). HCH have become of great public concern because the lindane batches used in the late forties contained appreciable concentrations of alpha-and beta-isomer. The alpha-isomer was found to induce liver tumors in rats and mice (2), the beta-isomer was found to have very low biodegradability and to be deposited in animal fat. Although the lindane batches used since the fifties were at least 99% pure gamma-isomer, a new discussion arose from controversial findings of a liver tumor-inducing potential of lindane itself.Chemically-induced tumors are now thought to be the result of a DNA damage succeeded by appropriate promotion (3). Most chemicals exert their activity by covalent interaction of a reactive metabolite with DNA in the target organ and are therefore called genotoxic. The metabolism of HCH involves the formation of olefins (1) and a subsequent epoxidation could result in the generation of an electrophilic species.Another group of tumor-enhancing agents, viz cocarcinogens and promoters, do not themselves react with DNA but apparently modulate one or several out of a variety of biochemical and biological steps related to the process of tumor formation. Such activities are also discussed for HCH. For instance, alpha-HCH was found to enhance the proliferation of putative preneoplastic cells in rat liver (4), and all HCH isomers are known to be inducers of drug-metabolizing enzymes (1), the alpha-isomer being more potent than lindane.It was the aim of this study to provide more information about the mechanism of tumor induction by HCH. For this reason it was examined whether the isomers of HCH can be metabolized in vivo to reactive metabolites able to reach and bind to liver DNA or whether the hepatocarcinogenicity is rather due to non-genotoxic effects. It seemed especially worthwhile to investigate whether the clear difference between the alpha-and the gamma-isomer with respect to biological effects and tumor induction (2) was reflected in their ability to bind to DNA, and whether the apparent difference in susceptibility of different strains of mice to the carcinogenicity of gamma-HCH (5 -7) can be based upon different levels of DNA binding.

Nitrosation of aspartic acid, aspartame, and glycine ethylester. Alkylation of 4-(p-nitrobenzyl)pyridine (NBP) in vitro and binding to DNA in the rat

“…DNA was isolated from a chromatin pellet according to Sagelsdorff et al (1983). The nucleo- tide analysis was performed according to Sagelsdorff et al (1988).…”

Quantitative Evaluation of DNA-Binding Data In Vivo for Low-Dose Extrapolations

“…Cell division seems to be an absolute requirement in carcinogenesis, and agents or processes which stimulate the rate ofDNA synthesis are often found to increase the tumor incidence. Some compounds most probab1y produce DNA adducts and stimulate cell division: hexach1orocyclohexane isomers could be named (Sagelsdorff et al 1983) and formaldehyde might also be an examp1e (Swenberg et al 1983). In both cases it is considered that the DNAbinding activity is low so that it would not a1one be sufficient to lead to a significant increase in tumor formation in a standard bioassay (Fig.…”

Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens

“…Forthis purpose, DNA is degraded, the natural nucleotides are separated from the nucleotide-carcinogen adducts, and the specific activity ofthe natural DNA constituents is determined. Only the radioactivity eluting without detectable optical density (too few molecules) can represent DNA binding (Sagelsdorff et al 1983).…”