The peroxisome proliferator nafenopin does not suppress hepatocyte apoptosis in guinea-pig liver in vivo nor in human hepatocytes in vitro |
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Authors: | Susan C Hasmall Neil H James Anthony R Soames Ruth A Roberts |
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Institution: | (1) Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, UK Fax: 0 (1) 625-517964 e-mail: Sue.Hasmall@CTL.ZENECA.com, GB |
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Abstract: | In rats and mice, nafenopin is a nongenotoxic hepatocarcinogen, which induces hepatic DNA synthesis and enzyme induction
both in vivo and in hepatocyte cultures in vitro. However, humans and guinea-pigs are considered to be non-responsive to the
liver growth effects of peroxisome proliferators (PPs). The ability to stimulate cell replication coupled with the ability
to suppress apoptosis is thought to underpin the carcinogenicity of nongenotoxic carcinogens such as PPs. Previous studies
in this laboratory have shown that in rats in vivo and in vitro nafenopin suppressed spontaneous hepatocyte apoptosis and
that induced by the physiological negative growth regulator transforming growth factors β1 (TGFβ1). In addition nafenopin
suppressed apoptosis in cultured hepatocytes from guinea-pig and hamster. The effects of PPs on apoptosis in human hepatocyte
cultures is not known. To correlate these previous in vitro findings to the known species differences in hepatocarcinogenicity
of PPs we have investigated the effects of nafenopin on guinea-pig liver growth in vivo. Also, we have examined the effects
of nafenopin on apoptosis in cultures of human hepatocytes, a valuable model for human risk assessment. Nafenopin did not
inhibit either spontaneous or TGFβ1 induced apoptosis in human hepatocytes in vitro. Administration of nafenopin to guinea-pigs
in vivo produced none of the changes seen previously in responsive species, such as rats and mice. There was no change in
liver/body weight ratio, peroxisomal volume of hepatocytes or DNA synthesis as determined by incorporation of bromodeoxyuridine
and there was no suppression of apoptosis. The lack of response to nafenopin in guinea-pigs in vivo and human hepatocytes
in vitro provides further evidence that these species may be refractory to the liver growth effects of PPs despite the ability
of guinea-pigs and humans to respond to PPs by alterations in lipid metabolism. The data presented add to our overall understanding
of species differences in response to the PP class of rodent nongenotoxic carcinogens.
Received: 9 June 1998 / Accepted: 21 September 1998 |
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Keywords: | Nafenopin Apoptosis Species differences Peroxisome proliferation |
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