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標題: Formation and removal of pentachlorophenol-derived protein adducts in rodent liver under acute, multiple, and chronic dosing regimens
作者: Tsai, C.H.
Lin, P.H.
Troester, M.A.
Rappaport, S.M.
關鍵字: pentachlorophenol;quinone;liver protein adducts;protein turnover;adduct stability;non-hodgkins-lymphoma;phenoxyacetic acids;chlorinated quinone;covalent binding;albumin adducts;hemoglobin;rats;exposure;dna;tetrachlorohydroquinone
Project: Toxicological Sciences
期刊/報告no:: Toxicological Sciences, Volume 73, Issue 1, Page(s) 26-35.
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 (Cl-4-1,2-BQ) and tetrachloro-1,4-benzoquinone (Cl-4-1,4-BQ) following reduction of cysteinyl adducts by Raney nickel and gas chromatography-mass spectrometry. Ratios of Cl-4-1,2-BQ to Cl-4-1,4-BQ adducts were much greater in mice (0.8-2) than in F344 rats (0.04-0.07), indicating that Cl-4-1,2-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.
ISSN: 1096-6080
DOI: 10.1093/toxsci/kfg057
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