The hepatocarcinogen methapyrilene but not the analog pyrilamine induces sustained hepatocellular replication and protein alterations in F344 rats in a 13-week feed study.
Methapyrilene (MPH) was a widely used antihistamine until it was found to produce hepatocellular carcinoma and cholangiocarcinoma in Fischer 344 rats. The structurally similar antihistamine pyrilamine (PYR) was marginally or noncarcinogenic in a similar study. The peroxisome proliferator Wy-14,643 was included in this study as a positive control. As part of a program to investigate the mechanisms whereby structurally similar chemicals produce different toxicities, we studied these three chemicals for the induction of cell proliferation in the liver of F344 rats. Male rats were treated for up to 13 weeks with feed dosed with MPH (HCl salt) at 0, 50, 100, 250, or 1000 ppm or PYR (maleate salt) at 1000 ppm to duplicate the route of administration and high-dose groups used in the carcinogenesis assay. In addition, the nongenotoxic hepatocarcinogen peroxisome proliferator Wy-14,643 was included as a positive cell-proliferating chemical. Cell proliferation was quantitated by measuring the incorporation of bromodeoxyuridine (BrDU) administered by osmotic minipump for 7 days and the appearance of proliferating cell nuclear antigen (PCNA) immunohistochemically. The BrDU-labeling index showed a large and sustained increase in rats treated with MPH at 250 and 1000 ppm, sustaining greater than 50% labeling in the higher dose group of 4-, 6-, and 13-week treatment groups. PYR at 1000 ppm demonstrated no significant increase in labeling above control levels at any time point. PCNA-labeling indexes showed similar but reduced increases for MPH and were comparable to control for the PYR dose groups. Two-dimensional gel electrophoresis was used for the detection of quantitative changes in gene expression and qualitative changes in the charges of specific mitochondrial and cytosolic proteins. Quantitative changes in 32 proteins induced by MPH and 39 changes induced by Wy-14,643 were detected throughout the 13-week study. Specific mitochondrial protein charge shifts were associated with high-dose MPH treatment that were not observed in animals treated with Wy-14,643. PYR induced no significant qualitative or quantitative protein alterations. Hepatocellular proliferation of the large magnitude observed following dietary administration of MPH, and not PYR may contribute to the mechanism of carcinogenesis of MPH.
Cunningham
M L
ML
Chemistry Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Pippin
L L
LL
Anderson
N L
NL
Wenk
M L
ML
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects*; D008297:Male; D008701:Methapyrilene / Q000633:toxicity*; D008930:Mitochondria, Liver / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D014176:Protein Biosynthesis; D011738:Pyrilamine / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D018809:Proliferating Cell Nuclear Antigen; D011743:Pyrimidines; C006253:pirinixic acid; D008701:Methapyrilene; D011738:Pyrilamine