Covalent binding of hexachlorobutadiene metabolites to renal and hepatic mitochondrial DNA

Abstract

The covalent binding of [14C]hexachlorobutadiene (HCBD) metabolites to DNA was investigated in mouse liver and kidney after application of a single oral dose of 30 mg/kg. A low level of binding of [14C]HCBD metabolites to nuclear DNA (nDNA) from kidney with a covalent binding index (CBI) of 27 was detectable, whereas nDNA from liver did not retain radioactivity significantly exceeding background activity (background CBInDNA = 6 and CBImtDNA = 60). Considerably higher binding of metabolites to mitochondrial DNA (mtDNA) from liver (CBI = 500) and kidney (CBI = 7500) could be demonstrated. Enzymatic hydrolysis followed by HPLC fractionation of mtDNA from mouse kidney revealed the presence of three radioactive compounds which may represent DNA bases altered by HCBD metabolites. The observed binding of HCBD metabolites to DNA constituents in vivo suggests that genotoxic mechanisms are operative in initiating HCBD nephrocarcinogenesis.