The potent hepatocarcinogen methapyrilene induces mutations in L5178Y mouse lymphoma cells in the apparent absence of DNA adduct formation

Abstract

The antihistamine methapyrilene hydrochloride has been shown to be a potent hepatocarcinogen in Fischer 344 rats. It has also been evaluated in a number of short-term in vivo and in vitro genotoxicity assays with conflicting results. We studied its ability to form DNA adducts in the L5178Y/TK+/- mouse lymphoma cells, an assay system in which methapyrilene is a moderately active mutagen and appears to induce mutations predominantly of chromosomal origin. Methapyrilene failed to induce formation of DNA adducts in L5178Y cell DNA at doses which induced mutations at the thymidine kinase locus. These data suggest that methapyrilene induces mutations in this system through an indirect genotoxic mechanism; e.g., via an oxidative mechanism or interaction with chromosomal proteins.