Formation and removal of pentachlorophenol-derived protein adducts in Rodent liver under acute, multiple, and chronic dosing regimens

Abstract

We investigated the kinetics of production and elimination of chlorinated quinone adducts of liver cytosolic proteins derived from pentachlorophenol (PCP), following oral administration under acute dosing (0-40 mg/kg body weight [bw] in Sprague-Dawley rats, 0-120 mg/kg bw in F344 rats, and 0-60 mg/kg bw in B6C3F1 mice), multiple dosing (0-60 mg/kg bw/day for 5 days in F344 rats and B6C3F1 mice), and chronic feeding (60 mg/kg bw/day for 6 months in F344 rats). We measured adducts of both tetrachloro-1,2-benzoquinone (Cl4-1,2-BQ) and tetrachloro-1,4-benzoquinone (Cl4-1,4-BQ) following reduction of cysteinyl adducts by Raney nickel and gas chromatography-mass spectrometry. Ratios Of Cl4-1,2-BQ to Cl4-1,4-BQ adducts were much greater in mice (0.8-2) than in F344 rats (0.04-0.07), indicating that Cl4-1,2-BQ is an important PCP-binding species in mice but not rats. Following acute administration of 20 mg PCP/kg bw to Sprague-Dawley rats and B6C3F1 mice, the time course of adduct elimination over 14 days followed biphasic kinetics, with a rapid phase representing at least 92% of the adduct burden. Using data from acute experiments, we predicted adduct levels in rats and mice after the multiple- and chronic-dosing regimens. The agreement between predicted and observed levels was good (intraclass correlation coefficients of predicted and observed pairs of logged adduct levels were 0.812-0.921). These results provide evidence that the kinetics of liver protein adducts were not influenced by the dosing regimen of PCP, a recognized toxicant of the liver.