The peroxisome proliferator nafenopin does lot suppress hepatocyte apoptosis in guinea-pig liver in vivo nor in human hepatocytes in vitro

Citation
Sc. Hasmall et al., The peroxisome proliferator nafenopin does lot suppress hepatocyte apoptosis in guinea-pig liver in vivo nor in human hepatocytes in vitro, ARCH TOXIC, 72(12), 1998, pp. 777-783
Citations number
42
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
ARCHIVES OF TOXICOLOGY
ISSN journal
0340-5761 → ACNP
Volume
72
Issue
12
Year of publication
1998
Pages
777 - 783
Database
ISI
SICI code
0340-5761(199812)72:12<777:TPPNDL>2.0.ZU;2-6
Abstract
In rats and mice, nafenopin is a nongenotoxic hepatocarcinogen, which induc es hepatic DNA synthesis and enzyme induction both in vivo and in hepatocyt e cultures in vitro. However, humans and guinea-pigs are considered to be n on-responsive to the liver growth effects of peroxisome proliferators (PPs) . The ability to stimulate cell replication coupled with the ability to sup press apoptosis is thought to underpin the carcinogenicity of nongenotoxic carcinogens such as PPs. Previous studies in this laboratory have shown tha t in rats in vivo and in vitro nafenopin suppressed spontaneous hepatocyte apoptosis and that induced by the physiological negative growth regulator t ransforming growth factors beta 1 (TGF beta 1). In addition nafenopin suppr essed apoptosis in cultured hepatocytes from guinea-pig and hamster. The ef fects of PPs on apoptosis in human hepatocyte cultures is not known. To cor relate 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 f or human risk assessment. Nafenopin did not inhibit either spontaneous or T GF beta 1 induced apoptosis in human hepatocytes in vitro. Administration o f nafenopin to guinea-pigs in vivo produced none of the changes seen previo usly in responsive species, such as rats and mice. There was no change in l iver/body weight ratio, peroxisomal Volume of hepatocytes or DNA synthesis as determined by incorporation of bromode-oxyuridine and there was no suppr ession of apoptosis. The lack of response to nafenopin in guinea-pigs in vi vo and human hepatocytes in vitro provides further evidence that these spec ies may be refractory to the liver growth effects of PPs despite the abilit y of guinea-pigs and humans to respond to PPs by alterations in lipid metab olism. The data presented add to our overall understanding of species diffe rences in response to the PP class of rodent nongenotoxic carcinogens.