Disease relevance of Nafenopin

• The ability of the peroxisome proliferator nafenopin to suppress or delay the onset of liver apoptosis was investigated using primary cultures of rat hepatocytes and the Reuber hepatoma cell line FaO [1].
• Treatment of animals after food restriction with nafenopin, a peroxisome proliferator and potent tumor promoter, produced only half as many hepatocellular adenomas and carcinomas as in animals fed unrestrictedly throughout their lifetime [2].
• When hyperplasia was induced by cyproterone acetate and nafenopin, the mitogenic response of the liver was not associated with an increased expression of c-jun or c-fos, despite the fact that the timing of the cell cycle was similar to that observed after partial hepatectomy [3].
• 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 [4].
• In addition, cultures that have been treated with the CYP102 inducer, nafenopin, are protected against PUFA toxicity [5].

High impact information on Nafenopin

• Malignant tumors in rats fed nafenopin, a hepatic peroxisome proliferator [6].
• 50 microM nafenopin reversibly maintained the viability of primary rat hepatocyte cultures which otherwise degenerated within 8 d of establishment [1].
• Co-addition of 50 microM nafenopin significantly reduced TGF beta 1-induced apoptosis by 50-60% [1].
• Co-addition of 50 microM nafenopin to TGF beta 1-treated FaO cultures significantly reduced the number of apoptotic cells detaching from the monolayer at 24 h [1].
• In contrast, nafenopin had no significant effect on FaO apoptosis induced by the DNA damaging agents etoposide and hydroxyurea [1].

Chemical compound and disease context of Nafenopin

• Apoptosis was also extensive in AH-130 cells treated with another PP such as nafenopin at 1 mM concentration and in human hepatoma HepG2 cells treated with clofibrate [7].
• Our earlier studies have revealed that direct hyperplasia induced by liver mitogens such as lead nitrate, ethylene dibromide, nafenopin and cyproterone acetate, unlike compensatory cell proliferation induced by partial hepatectomy and CCl4, does not support the formation of enzyme-altered islands induced by chemical carcinogens in the liver [8].
• DNAs from 27 samples, which included adenomas, carcinomas in situ, and adenocarcinomas arising in azaserine-treated rats and corn oil-gavaged rats along with a nafenopin-induced rat pancreatic adenocarcinoma were examined for mutation of c-Ki-ras at codons 12, 13, and 61 by using the polymerase chain reaction [9].
• PB or NAF treatment for 7 days produced moderate increases of liver DNA (15% or 25-28%, respectively) along with pronounced hypertrophy [10].
• At higher concentrations statistically significant increases of chromosomal aberrations (nafenopin: 100 microM; ciprofibrate: > or = 100 microM) and micronuclei (ciprofibrate: > or = 250 microM) were also found [11].

Biological context of Nafenopin

• The patterns of cell proliferation induced by these agents were further compared with those induced by a single dose of nafenopin (NAF), a direct mitogen which does not induce liver TNF-alpha messenger RNA (mRNA) [12].
• However, Nafenopin depressed HTC net population expansion via a suppression of cell death coupled to a more marked inhibition of RDS [13].
• Role of oxidative stress in age dependent hepatocarcinogenesis by the peroxisome proliferator nafenopin in the rat [14].
• Prolonged NAF treatment enhanced cell number in normal liver by 25%, while PPF and liver tumors were amplified at least 100-fold [15].
• Nafenopin also increased FaO cell growth but, surprisingly, retarded the growth of both HTC and RH1 cells [13].

Anatomical context of Nafenopin

• The responses of a series of rat hepatoma cell lines (FaO, HTC, RH1) to the rodent non-genotoxic hepatocarcinogen and per-oxisome proliferator (PP) Nafenopin were studied to determine if this PP acts with EGF, a naturally occurring liver growth regulator, to perturb the balance between mitosis and apoptosis [13].
• However, the light microscopic autoradiograms revealed the [35S]sulfate incorporation as follows: azaserine-induced transplantable pancreatic carcinoma greater than nafenopin-induced transplantable pancreatic carcinoma greater than normal pancreas [16].
• Finally, nafenopin appeared to delay the appearance of gamma-glutamyltranspeptidase activity within the cultured cells [17].
• A single dose of the peroxisome proliferator (PP) nafenopin (NAF) induced the enzyme predominantly in hepatocytes around the central venules and cell replication mainly in the periportal areas [18].
• The anti-mouse liver cytosolic epoxide hydrolase antibody was found to precipitate the whole trans-stilbene oxide hydrolase activity also from liver cytosol of nafenopin-treated mice, which indicates the presence of a single cytosolic epoxide hydrolase following induction [19].

Associations of Nafenopin with other chemical compounds

• The biochemical effects in the livers of male rats of prolonged administration of the experimental hepatocarcinogen nafenopin, a hypolipidemic agent and peroxisome proliferator, were compared to those of another experimental liver carcinogen, phenobarbital, which acts as a neoplasm promoter [20].
• Therefore, in the present study we evaluated the effect of two potent peroxisome proliferators, nafenopin and WY-14,643, on Kupffer cell activation in vivo [21].
• In guinea pig hepatocytes transfected with control plasmids and treated with 50 microM nafenopin in the absence or presence of the RXR ligand, 9-cis-retinoic acid (5 microM) gave only a 1.7 +/- 1.5- or 3.3 +/- 1.5-fold induction in CIPCO, respectively [22].
• Deletion analysis revealed that the responsive region for both DHEA and nafenopin was between -108 and -60 relative to the transcription start site [23].
• In addition, nafenopin also caused a pronounced and time-dependent increase in palmitoyl-CoA beta-oxidation activity but was found to have only a weak stimulating effect on replicative DNA synthesis (2-fold) when compared to that of epidermal growth factor (6.5-fold) [24].

Gene context of Nafenopin

• Role for tumor necrosis factor alpha receptor 1 and interleukin-1 receptor in the suppression of mouse hepatocyte apoptosis by the peroxisome proliferator nafenopin [25].
• The induction of DNA synthesis and the suppression of apoptosis in response to nafenopin was abrogated completely by blocking antibodies to TNFR1 but not to TNFR2 [25].
• In addition, anti-IL-1 receptor, type 1/p80 (IL-1R) antibodies were able to abrogate the response to nafenopin [25].
• TGF beta, a physiological negative regulator of liver growth, was able to inhibit the nafenopin/EGF-stimulated colony formation at 0.25 ng/ml, a concentration below that required for TGF beta-induced hepatocyte apoptosis [26].
• The neutralization of TNF alpha using anti-TNF alpha antibodies abrogated significantly (P < or = 0.01) the suppression of apoptosis by the PP, nafenopin [27].

Analytical, diagnostic and therapeutic context of Nafenopin

• The increased PCR of T4 cannot be explained by an increase in deiodination activity, since the major 5'D pathways are inhibited after nafenopin treatment, and the urinary clearance rate is not modified [28].
• Western blot analyses showed that nafenopin and TGFbeta1 had opposing effects on cyclin-dependent kinase 4 (CDK4) protein: nafenopin elevated CDK4 compared with controls, whereas TGFbeta1 caused a reduction [29].
• The repeated oral administration of nafenopin, a hypolipidaemic compound, at a dose of 100 mg/kg to male C57BL/6, DBA/2, Balb c and C3H mice caused an increase in the specific activity of liver cytosolic epoxide hydrolase, the activity of microsomal epoxide hydrolase was also increased in all except the C3H mice [30].
• HPLC analysis of bile samples revealed that only about 10% of the radioactivity recovered in bile was associated with non-metabolized nafenopin and approx. 90% with more polar metabolites [31].
• Immunohistochemistry indicated that the localization of plaques containing connexin 32 was not affected in hepatocytes by nafenopin [32].

References