Examination of genotoxicity, toxicity and morphologic alterations in hepatocytes following in vivo or in vitro exposure to methapyrilene.
The antihistamine methapyrilene (MP) was widely used as a component of cold, allergy and sleep-aid medications in the 1970s until it was identified as a potent rat liver carcinogen. MP does not induce positive responses in most short-term genotoxicity assays, which suggests that it is carcinogenic by a non-genotoxic mechanism. We have evaluated the potential of MP to induce unscheduled DNA synthesis (UDS), a genetic end point and S-phase synthesis (SPS), and indicator of cell proliferation, in Fischer-344 (F344) rat and B6C3F1 mouse liver. We also examined the response of MP in hepatocytes from two species treated in vitro. MP failed to induce UDS in rat or mouse liver following in vivo treatment, or in hepatocytes from rat and adult human treated in vitro. Control rats and mice yielded less than 0.3% of cells in S-phase (%S). In contrast, MP induced significant elevations in SPS both in male F344 rat (6.3%S) and female B6C3F1 mice (1.4%S). In the male rat, sorbitol dehydrogenase (SDH), bilirubin, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) showed elevations of 9-, 10-. 17- and 28-fold over controls respectively, indicating that significant hepatotoxicity was induced by MP. This was confirmed by histopathologic examination, which revealed significant periportal and focal necrosis followed by an increased presence of mitotic figures. These results indicate that MP is not genotoxic in rat liver, but is a potent inducer of hepatic cell proliferation by inducing toxicity and subsequent regeneration, which may be an important mechanism of hepatocarcinogenesis.
Steinmetz
K L
KL
Toxicology Laboratory, SRI International, Menlo Park, CA 94025.
Tyson
C K
CK
Meierhenry
E F
EF
Spalding
J W
JW
Mirsalis
J C
JC
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000631:Aminopyridines / Q000633:toxicity*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002273:Carcinogens; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D006801:Humans; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008701:Methapyrilene / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011916:Rats, Inbred F344
D000631:Aminopyridines; D002273:Carcinogens; D015073:2-Acetylaminofluorene; D008701:Methapyrilene; D007064:L-Iditol 2-Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin