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The coordinate regulation of DNA synthesis and suppression of apoptosis was investigated in a rat hepatocyte cell culture system which supports high level induction of DNA synthesis by the peroxisome proliferator, methylclofenapate (MCP) (Plant, N.J. et al., 1998, Carcinogenesis, 19, 925-931). The peroxisome proliferators are hepatocyte mitogens in chemically defined media: glucocorticoid-induced PPARalpha is linked to peroxisome proliferator mitogenesis (Plant, N.J. et al., 1998, Carcinogenesis, 19, 925-932). Phenobarbital (PB) induced moderate induction of DNA synthesis (200-300% of control), but the peak of induction was 40 h after treatment. In hepatocytes that had undergone DNA synthesis, PB increased the proportion of binucleates by 200-300%. Both PB and MCP were able to suppress apoptosis in a dose-dependent manner, while the endogenous mitogen epidermal growth factor failed to suppress apoptosis. The suppression of apoptosis by MCP was reversible; withdrawal of MCP led to rapid induction of apoptosis. The presence of hydrocortisone is required for suppression of apoptosis by peroxisome proliferators, but not for PB. MCP failed to suppress apoptosis in primary cultures of guinea-pig hepatocytes. Comparison of the stability of hepatocytes labelled with bromodeoxyuridine (BrdUrd) and [3H]thymidine revealed that approximately 40% of cells labelled with BrdUrd were lost over a period of 14 days, whereas cells labelled with thymidine remained stable over this period. Hepatocytes were therefore treated with MCP, labelled with [3H]thymidine, maintained for 14 days, and peroxisome proliferator withdrawn. While the apoptotic index in unlabelled cells was 1.7%, no apoptosis was detected in labelled cells. In order to compare the mechanism of suppression of apoptosis, hepatocytes were cultured in the presence of either PB or MCP for 14 days. When MCP was substituted for PB in cells cultured in the presence of PB, the monolayer was maintained, but when PB was used to replace MCP in cells cultured in the presence of MCP, the monolayer of hepatocytes degenerated rapidly. The results demonstrate mechanistic differences in the coordinate regulation of cell growth and apoptosis in hepatocytes by PB and MCP.

carcinogenesis

The coordinate regulation of DNA synthesis and suppression of apoptosis is differentially regulated by the liver growth agents, phenobarbital and methylclofenapate