Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of long-term administration of nafenopin, a potent hypolipidemic drug with marked hepatomegalic and peroxisome-proliferative properties, were studied in wild-type (Csa strain) and acatalasemic (Csb strain) mice. Nafenopin was administered in the diet at a concentration of 0.1% during the first 12 months and then at 0.05% until the termination of the experiment at 20 months. By 56 weeks, 100% mortality occurred in both male and female wild-type mice, whereas the mortality rate in acatalasemic mice was approximately 50%. Between 18 and 20 months of the experiment, 9 of 9 male and 12 of 12 female acatalasemic mice that survived chronic nafenopin treatment developed hepatocellular carcinomas, some of which metastasized to the lungs. None of the 15 male and 15 female acatalasemic controls developed liver cancers. Numerous peroxisomes were seen in the lung metastases of these hepatocellular carcinomas on electron microscopic examination; in contrast the number of peroxisomes in primary liver tumor cells varied considerably. The hepatocarcinogenicity of nafenopin strongly suggests the need for long-term studies with other hypolipidemic drugs that cause hepatomegaly and peroxisome proliferation to clarify the role, if any, of peroxisome proliferation in liver carcinogenesis.
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PMID:Hepatocellular carcinomas in acatalasemic mice treated with nafenopin, a hypolipidemic peroxisome proliferator. 17 2

The mitogenic effects of peroxisome proliferating agents have been implicated in their carcinogenicity. WY-14,643 stimulates an increase in hepatocellular DNA replication that persists with continued administration, but it is unclear if other peroxisome proliferators share this property. In these studies, WY-14,643 was compared to clofibric acid, nafenopin and LY171883 given to rats in the diet for up to 30 days. DNA replication in the rat liver was quantified by immunohistochemical methods after continuous s.c. infusion of bromodeoxyuridine by osmotic minipump. During the first 7 days of treatment, WY-14,643 (0.1% in diet) and nafenopin (0.05%) increased the percentage of bromodeoxyuridine-labeled hepatocytes to greater than 50%, from 3% in controls. Clofibric acid (0.5%) and LY171883 (0.3%) increased the labeling to approximately 33%. The replicative response to each of the compounds was localized primarily to the periportal region of the liver lobule. The time-course of replication induced by clofibric acid and WY-14,64.3 was examined over 3 day intervals. The peak of replication in response to clofibric acid occurred during days 4-6, whereas the effect of WY-14,643 peaked during days 1-3 and was much greater than clofibric acid. The replicative response to WY-14,643 persisted through 30 days at dietary concentrations of 0.1 and 0.005%. Nafenopin, LY171883 and clofibric acid were without effect on DNA replication on days 28-30 even though the hepatomegaly and induction of peroxisomal beta-oxidation persisted. Thus, under the conditions of these experiments, the persistent replicative effect through 30 days was unique to WY-14,643. Although sustained replication in the general population of hepatocytes may be involved in the carcinogenesis of WY-14,643, it does not appear to be a factor in the hepatocarcinogenesis of the other peroxisome proliferators.
Carcinogenesis 1991 Sep
PMID:Hepatocellular DNA synthesis in rats given peroxisome proliferating agents: comparison of WY-14,643 to clofibric acid, nafenopin and LY171883. 189 15

The effect of nafenopin and phenobarbitone upon the distribution of gamma-glutamyltranspeptidase activity and epoxide hydrolase antigenic sites in the liver and upon the development of enzyme-altered foci during hepatocarcinogenesis have been compared. Phenobarbitone induced gamma-glutamyltranspeptidase activity in perilobular hepatocytes. Nafenopin did not alter the distribution of this enzyme. Both compounds appeared to induce epoxide hydrolase; phenobarbitone increased the enzyme content of centrilobular cells, whilst nafenopin altered immunostaining mainly in portal regions. Hepatic lesions were induced by treating one day-old rats with diethylnitrosamine. Phenobarbitone and nafenopin were then administered in the diet upon weaning. Animals were killed after either 2, 4 or 8 weeks feeding and liver sections were stained for the two enzymes. Only sections from nitrosamine-treated animals contained enzyme-altered foci. In general, gamma-glutamyltranspeptidase-containing foci stained also for epoxide hydrolase; but many hydrolase-positive foci did not stain for gamma-glutamyltranspeptidase activity. Phenobarbitone treatment stimulated the formation of enzyme-altered foci. This effect was more marked in male animals. Nafenopin treatment suppressed the development of foci at all time points, such that less hepatic lesions were seen than in animals which received only diethylnitrosamine. The results cast doubt upon the generality of gamma-glutamyltranspeptidase as a marker for preneoplastic lesions within the liver.
Carcinogenesis 1984 Jan
PMID:Inhibitory effect of nafenopin upon the development of diethylnitrosamine-induced enzyme-altered foci within the rat liver. 614 87

The effect of nafenopin upon primary cultures of adult rat hepatocytes has been investigated. Nafenopin treatment resulted in a proliferation of peroxisomes within the cultured cells. This proliferation was the result of an increase in both the number and size of the peroxisomes. Nafenopin treatment also caused an increased level of thymidine incorporation into the cultures, which was a consequence of replicative DNA synthesis rather than DNA repair. Finally, nafenopin appeared to delay the appearance of gamma-glutamyltranspeptidase activity within the cultured cells. Consequently three effects of nafenopin upon the liver were reproduced using monolayers of adult rat hepatocytes, which suggests that this culture system may be useful to further investigate the molecular processes underlying peroxisome proliferation, and their involvement in the hepatocarcinogenicity of peroxisome proliferators.
Carcinogenesis 1984 Aug
PMID:Use of primary cultures of adult rat hepatocytes to investigate mechanisms of action of nafenopin, a hepatocarcinogenic peroxisome proliferator. 614 7

Previously, we have shown that the peroxisome proliferator (PP), nafenopin, induces S-phase in rat hepatocytes and suppresses apoptosis in hepatocytes from both rat and guinea-pig. Here, we confirm and extend these findings by defining the time course of growth perturbation and by correlating this with species differences in loss of gap junctional intercellular communication (GJIC). GJIC is associated with nongenotoxic carcinogenesis, possibly reflecting a tumour suppresser role of the connexins. Fluorescence microscopy of Hoechst 33258-stained rat or guinea-pig hepatocyte monolayers showed 1% apoptosis during the first 8 h of culture, peaking to 2-2.5% at 20-24 h. Nafenopin suppressed apoptosis compared with controls in both rat and guinea-pig, measured at 20 h and 24 h onwards, respectively. The induction of S-phase in rat hepatocytes by nafenopin could be detected as early as 4 h after compound addition whereas S-phase was not altered by nafenopin in guinea-pig hepatocytes. Intercellular communication as measured by intercellular transfer of microinjected Lucifer Yellow CH was observed during the first 14 h of primary rat hepatocyte culture peaking at a maximum value of 88 +/- 3.0% after 7 h. In hepatocyte cultures from guinea-pig, dye-coupling levels were maintained between 88 +/- 3.0 and 93 +/- 3.0% within 2-10 h of culture and by 12 h showed only a slight decrease to 72 +/- 3.0%. In the rat, significant inhibition was observed at 4 h after administration of nafenopin since GJIC was reduced by 20 +/- 5% compared with vehicle control. By contrast, in the presence of nafenopin, the level of dye-coupling between guinea-pig hepatocytes did not decrease but remained between 85 +/- 5 and 93 +/- 3.0%, similar to that observed in control guinea-pig cultures. The data obtained contribute to our understanding of the role of GJIC inhibition in the perturbation of cell survival and proliferation caused by nongenotoxic hepatocarcinogens.
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PMID:The rodent nongenotoxic hepatocarcinogen and peroxisome proliferator nafenopin inhibits intercellular communication in rat but not guinea-pig hepatocytes, perturbing S-phase but not apoptosis. 970 83

Induction of liver cancer by peroxisome proliferators such as nafenopin is frequently associated with increased liver growth, increased DNA synthesis and suppression of apoptosis. The cytokine, tumour necrosis factor alpha (TNF alpha), and non-parenchymal liver cells have been implicated in mediating the hepatic response to peroxisome proliferators. Here, we have investigated the dependency of the hepatocyte response to peroxisome proliferators on non-parenchymal cells, a major source of hepatic cytokines. Addition of non-parenchymal cells, or conditioned medium from non-parenchymal cell cultures, increased DNA synthesis (220% and 270% of control, respectively) and suppressed transforming growth factor beta(1)-induced hepatocyte apoptosis (32% and 54% of control, respectively). Removal of non-parenchymal cells from normal hepatocyte cultures prevented both the nafenopin- and TNF alpha-induced increase in DNA synthesis and suppression of hepatocyte apoptosis; this response was restored by returning non-parenchymal cells to the purified hepatocytes. TNF alpha was detected in the medium of non-parenchymal cell (3-15 pg/ml) and normal hepatocyte cultures (25-100 pg/ml) by bioassay using L929 cells. However, the contribution of TNF alpha released from non-parenchymal cells was small compared with that released spontaneously by hepatocytes. Nafenopin significantly increased the release of TNF alpha from non-parenchymal cells to 56 +/- 18 pg/ml, but had little effect on TNF alpha release by hepatocytes. However, the concentration of exogenous TNF alpha required to elicit a response in hepatocytes was 100 pg/ml and above. These data provide evidence that hepatic non-parenchymal cells are permissive for the growth response of hepatocytes in vitro to peroxisome proliferators and this may be mediated, at least in part by TNF alpha. However, the levels of TNF alpha released spontaneously or in response to peroxisome proliferators are insufficient per se to induce a growth response.
Carcinogenesis 2000 Dec
PMID:Role of hepatic non-parenchymal cells in the response of rat hepatocytes to the peroxisome proliferator nafenopin in vitro. 1113 4