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Lack of comitogenicity by the peroxisome proliferator hepatocarcinogens, Wy-14,643 and clofibric acid.

Hepatocyte replication is an early biological response in rodents following administration of peroxisome proliferators (PP); however, the mechanism for this response is unknown. This study examined two PP, Wy-14,643 and clofibric acid (CA), for mitogenic activity on primary hepatocyte cultures, both as direct acting mitogens and as indirect modulators (co-mitogens) of two hepatocyte growth factors, epidermal growth factor (EGF), and transforming growth factor-beta (TGF-beta). Primary hepatocytes were isolated from male F344 rats, seeded on collagen-coated coverslips, and incubated with increasing concentrations of Wy-14,643 or CA. Tritiated thymidine was coadministered to identify the percentage of hepatocytes involved in replicative DNA synthesis (labeling index, LI). In the absence of PP, rat hepatocytes in vitro were markedly sensitive to the mitogenic stimulus of EGF (LI, approximately 55%; versus control, approximately 1%), a mitogenic response abolished by increasing concentrations of TGF-beta. Marginal, direct mitogenicity (LI twofold over controls) was observed for Wy-14,643 (mitogenic as low as 0.1 microM). CA, a PP considerably less mitogenic in vivo than Wy-14,643, was not mitogenic in primary hepatocytes. Neither Wy-14,643 nor CA exhibited comitogenic activity with EGF or EGF/TGF-beta. Thus, while some PP may exhibit minor direct mitogenic activity in primary hepatocyte cultures, factors other than the interactions with the potent hepatocyte growth factors EGF or TGF-beta appear to modulate the strong mitogenic response of these hepatocarcinogens following administration to rodents.