Dose-specific production of chlorinated quinone and semiquinone adducts in rodent livers following administration of pentachlorophenol.
Production of chlorinated quinoid metabolites was investigated in the livers of Sprague-Dawley rats and B6C3F1 mice following single oral administration of pentachlorophenol (PCP) (0-40 mg/kg body weight) and in male Fischer 344 rats, following chronic ingestion of PCP at 1,000 ppm in the diet for 6 months (equivalent to 60 mg PCP/kg body weight/day). Analyses of the rates of adduction in the livers of Sprague-Dawley rats and B6C3F1 mice suggested that the production of tetrachloro-1,2-benzosemiquinone (Cl4-1,2-SQ) adducts was proportionally greater at low doses of PCP (less than 4-10 mg/kg body weight) and was 40-fold greater in rats than in mice. Production of tetrachloro-1,4-benzoquinone (Cl4-1,4-BQ) adducts, on the other hand, was proportionally greater at high doses of PCP [greater than 60-230 mg/kg body weight] and was 2- to 11-fold greater in mice than in rats over the entire range of dosages. A mathematical model employed these data to predict the rates of daily adduct production and steady state levels of PCP-derived quinone and semiquinone adducts in rats and mice. To evaluate predictions of the model, levels of PCP-derived adducts at steady state were investigated in the livers of male Fischer 344 rats chronically ingesting 60 mg PCP/kg body weight/day. Levels of total Cl4-1,4-BQ-derived adducts in liver cytosolic proteins (Cp) (22.0 nmol/g) and in liver nuclear proteins (Np) (3.07 nmol/g) were comparable to those of model predictions (15.0 and 3.02 nmol/g for Cp and Np, respectively). Overall, these results suggest that species differences in the metabolism of PCP to semiquinones and quinones were, in part, responsible for the production of liver tumors in mice but not rats in chronic bioassays.
Department of Environmental Sciences and Engineering, School of Pharmacy, University of North Carolina, Chapel Hill 27599, USA.
P H
PH
Lin
S
S
Waidyanatha
G M
GM
Pollack
J A
JA
Swenberg
S M
SM
Rappaport
D000818:Animals; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002703:Chloranil / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D010416:Pentachlorophenol / Q000378:metabolism* / Q000633:toxicity; D011809:Quinones / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002273:Carcinogens; D011809:Quinones; D002703:Chloranil; D010416:Pentachlorophenol