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Species differences in response to peroxisome proliferators correlate in vitro with induction of DNA synthesis rather than suppression of apoptosis
Zeneca Central Toxicology Laboratory Aldcrley Park, Macclesfield, SK10 4TJ, UK
1To whom correspondence should be addressed
Tumorigenesis caused by the peroxisome proliferator (PP) class of non-genotoxic hepatocarcinogens is species restricted; rat and mouse are considered responsive whereas the available evidence suggests that humans, non-human primates, dogs, hamsters and guinea, pigs are non-responsive. We have demonstrated previously that the PP, nafenopin can suppress rat hepatocyte apoptosis both in vitro and in vivo. Here we describe the ability of nafenopin to suppress apoptosis in mouse, hamster, guinea pig and rat hepatocytes and induce S-phase in mouse and rat hepatocytes. Hepatocyte monolayers from all species examined degenerated rapidly in culture. However, nafenopin (50 µM) reversibly maintained the viability of both rat and mouse hepatocytes. This maintenance was associated with a decrease (P 
0.01) in the number of hepatocytes displaying chromatin condensation patterns characteristic of apoptosis. Treatment of rat and mouse monolayers with 5 ng/ml transforming growth factor-ß1(TGFß1) induced high levels of apoptosis (P 0.01); co-addition of nafenopin suppressed this induced apoptosis (P 0.01). TGFß1 also induced apoptosis in hamster and guinea pig hepatocytes (P 0.01) and unexpectedly nafenopin was able to suppress this induced apoptosis (P 0.01) as well as reversibly maintaining the viability of hamster and guinea pig hepatocyte monolayers. Thus, all the species examined responded to nafenopin by a suppression of both spontaneous and TGFß1-induced apoptosis. In contrast, only rat and mouse hepatocytes showed an induction of S-phase in response to nafenopin (P 0.01). Certain key experiments were repeated using the PPs methyl clofenapate (MCP) (100 µM) and Wy-14, 643 (10 µM). Both were able to suppress spontaneous and TGFß1-induced apoptosis in rat and guinea pig hepatocytes although the effects of MCP were weak (P 0.05) compared with nafenopin or Wy-14 643 (P 0.01). The rat and mouse liver tumour promoter, phenobarbitone (PB) was assessed also. Rat hepatocytes responded to PB with a suppression of apoptosis and an induction of S-phase (P 0.01). Hamster and guinea pig cells gave no response in the S-phase assay and exhibited no suppression of either spontaneous or TGFß1-induced apoptosis. Interestingly, nafenopin suppressed the apoptosis induced by the DNA damaging drugs, etoposide and hydroxyurea (P 0.01) suggesting that PPs can impact on diverse apoptosis signalling pathways. Overall, species differences in response to the non-genotoxic hepatocarcinogens studied, correlate with induction of DNA synthesis rather than with suppression of apoptosis. The data extend ourknowledge of the mechanisms of species differences in non-genotoxic hepatocarcinogenesis, posing interesting questions on the relative roles of apoptosis and DNA synthesis in carcinogenisis.
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