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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg057
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received December 18, 2002; accepted February 4, 2003
© 2003 Society of Toxicology

Biotransformation and Toxicokinetics

Formation and Removal of Pentachlorophenol-Derived Protein Adducts in Rodent Liver Under Acute, Multiple, and Chronic Dosing Regimens

Chin-Hsiang Tsai 1, Po-Hsiung Lin 2, Melissa A. Troester 1, Stephen M. Rappaport 1*

1 Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7400
2 Department of Environmental Engineering, National Chung-Hsing University, Taichung, Taiwan

* To whom correspondence should be addressed. E-mail: stephen_rappaport{at}unc.edu.


  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 wt in Sprague-Dawley rats, 0-120 mg/kg body wt in F344 rats, and 0-60 mg/kg body wt in B6C3F1 mice), multiple dosing (0-60 mg/kg body wt/day for 5 days in F344 rats and B6C3F1 mice), and chronic feeding (60 mg/kg body wt/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 body wt to Sprague-Dawley rats and B6C3F1 mice, the time course of adduct elimination over 14 d 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 was not influenced by the dosing regimen of PCP, a recognized toxicant of the liver.

Pentachlorophenol, quinone, liver protein adducts, protein turnover, adduct stability .


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