Dose-dependent induction of GST-P+ staining foci by the rat hepatocarcinogen methapyrilene in the medium-term bioassay.
Previous studies have demonstrated that methapyrilene hydrochloride (MP) is a rat-specific nongenotoxic carcinogen which induces liver tumors in a dose-dependent manner following chronic exposure in the diet. This study was conducted to determine the dose response of MP in the medium-term bioassay and to compare the response to tumor incidence. Two weeks following a single initiating dose of diethylnitrosamine (DEN), male F344 rats were administered MP at doses of 0, 62.5, 125, 250, or 1000 ppm in the diet for 6 weeks. A 2/3 partial hepatectomy was performed 3 weeks post-DEN. At termination, sections from the remaining three lobes were stained with GST-P antibody. Number and size of foci were measured using an image analysis system with a digitizing board. MP induced a dose-dependent increase in the number of GST-P+ foci/cm2 (0 ppm = 0.85 foci/cm2; 62.5 ppm = 1.29 foci/cm2; 125 ppm = 1.59 foci/cm2; 250 ppm = 6.55 foci/cm2; 1000 ppm = 28.23 foci/cm2). A significantly greater number of foci were observed in the caudate lobe than in the anterior and posterior lobes. The size of individual foci was largely unaffected. This study demonstrates a strong correlation between foci induction and tumor incidence and suggests that this assay may have utility in predicting dose responses for the chronic bioassay.
Horn
D M
DM
Toxicology Research Laboratories, Eli Lilly and Company, Greenfield, Indiana 46140, USA.
Jordan
W H
WH
Holloway
D C
DC
Smith
W C
WC
Richardson
F C
FC
D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal; D002273:Carcinogens / Q000633:toxicity; D004032:Diet; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000737:chemistry* / Q000378:metabolism; D006498:Hepatectomy; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D007091:Image Processing, Computer-Assisted; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D008701:Methapyrilene / Q000008:administration & dosage / Q000633:toxicity*; D010920:Placenta / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D013194:Staining and Labeling
D000911:Antibodies, Monoclonal; D002273:Carcinogens; D006634:Histamine H1 Antagonists; D004052:Diethylnitrosamine; D008701:Methapyrilene; D005982:Glutathione Transferase