title: 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.
authors.affiliation: Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina, Chapel Hill 27599-7400, USA.
authors.forename: Chin-Hsiang
authors.initials: CH
authors.lastname: Tsai
authors.forename: Po-Hsiung
authors.initials: PH
authors.lastname: Lin
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Rappaport
mesh_terms: D000465:Algorithms; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D004785:Environmental Pollutants / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000378:metabolism*; D008297:Male; D015233:Models, Statistical; D010416:Pentachlorophenol / Q000008:administration & dosage / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry*; D011809:Quinones / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D004785:Environmental Pollutants; D011506:Proteins; D011809:Quinones; D010416:Pentachlorophenol