Microsomal activation of chlordane isomers to derivatives that irreversibly interact with cellular macromolecules

Abstract

Incubation of ¹⁴ C‐labeled cis and trans isomers of chlordane with cofactor‐fortified mouse hepatic microsomes resulted in binding of insecticide‐derived material to endogenous protein and RNA and to added DNA. The microsomes were prepared from male C57BL/6J mice. Chlordane is known to cause hepatocellular carcinoma in a similar strain.

The highest concentrations of radioactive material bound to protein, followed by RNA and DNA. The cis isomer produced greater amounts of bound radioactivity, while binding from trans‐chlordane was slight and, in the case of DNA, not detectable.

Investigation of the effect of microsomal enzyme induction by chlordane isomers and phenobarbital on the yield of bound, chlordane‐derived material gave mixed results. Generally, use of induced microsomes increased binding to protein and DNA and had no effect on binding to RNA. The inducers caused increased mixed‐function oxidase activity, cytochrome P‐450 content, and epoxide hydratase activity in experimental microsomes. Omission of the NADPH generating system from microsomal preparations had a variable effect on binding. Inhibition of epoxide hydratase reduced cis‐chlordane‐related binding to DNA to unmeasurable levels.

The irreversible interaction did not seem to involve oxychlordane, but other epoxide metabolites may be involved.