griseofulvin and Hyperplasia

Chronic griseofulvin (GF) feeding induces preneoplastic foci followed by hepatocellular carcinoma in the mouse liver. Our previous study suggested that GF-induced hepatocellular proliferation had a different mechanism from that of peroxisome proliferator (PP)-induced direct hyperplasia. The GF-induced hepatocellular proliferation was mediated through activation of immediate early genes such as Fos, Jun, Myc, and NFKB. In contrast, PP-induced direct hyperplasia does not involve activation of any of these immediate early genes. It has been shown that nuclear hormone receptors including peroxisome proliferator activated receptors (PPARs) and retinoid x receptors (RXRs) play important roles in mediating the pleiotropic effects of PPs. To examine the possible roles of PPARs and RXRs during non-PP-induced hepatocellular proliferation and the interaction between PP and non-PP-induced proliferation, we have studied the expression of the PPAR and RXR genes in the GF model using northern blot hybridizations and gel retardation assays. The data showed that the expression of PPARalpha and RXRalpha genes was down-regulated in the livers containing preneoplastic nodules and in the liver tumors induced by GF. The mRNA down-regulation was accompanied by a decrease in the amount of nuclear protein-bound to peroxisome proliferator and retinoic acid responsive elements. Down-regulation was also associated with the suppressed expression of the PPARalpha/RXRalpha target genes (i.e., acyl-Co oxidase and cytochrome P450 4A1) and the catalase gene. The RXR-gamma gene was also down-regulated, but the RARalpha, beta, and gamma and PPARbeta and gamma genes were up-regulated. These results indicated that the hepatocarcinogenesis induced by GF is accompanied by suppression of the PPARalpha/RXRalpha-mediated direct hyperplasia pathway. The differential expression of these nuclear hormone receptors reveals a new aspect for understanding the individual roles and intercommunication of PPAR, RXR, and RAR isoforms in the liver.

Topics: Acyl-CoA Oxidase; Animals; Carcinoma, Hepatocellular; Catalase; Cell Nucleus; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Genes, fos; Griseofulvin; Hyperplasia; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C3H; Mixed Function Oxygenases; NF-kappa B; Oxidoreductases; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Retinoid X Receptors; Transcription Factor AP-1; Transcription Factors

Topics: Animals; Cytoskeleton; Griseofulvin; Hyperplasia; Immunohistochemistry; Intermediate Filament Proteins; Intermediate Filaments; Keratins; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C3H; Microscopy, Electron; Neoplasm Proteins

Topics: Animals; Griseofulvin; Histocytochemistry; Hyperplasia; Liver; Mice; Mice, Nude

Hepatic hyperplastic nodules induced in mice by long-term griseofulvin administration were examined for selected microsomal activities and responses to enzyme inducers. Despite a decrease in microsomal cytochrome P-450 in hyperplastic nodules, aminopyrine N-demethylase was at control levels. Benzopyrene hydroxylase activity was slightly lower in microsomes derived from hyperplastic nodules than in those of control liver. Reduced nicotinamide adenine dinucleotide-cytochrome b5 reductase was at control level, but reduced nicotinamide adenine dinucleotide- and reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductases and the NADPH-ferricyanide reductase were increased. NADPH-supported lipid peroxidation was lower in microsomes from hyperplastic nodules than in those from control liver, whereas microsomal stearoyl coenzyme A desaturase activity was almost doubled in the nodules. NADPH-cytochrome c reductases isolated and semipurified from hyperplastic nodule and from control liver microsomes showed almost identical affinity for NADPH. Microsomal enzymes of hyperplastic nodules responded readily to phenobarbital induction, but sodium dodecyl sulfate-polyacrylamide gel electrophoresis disclosed differences in the polypeptide patterns in the molecular weight range from 47,000 to 54,000 between microsomes derived from hyperplastic nodules and control livers.

Topics: Animals; Cytochrome P-450 Enzyme System; Cytochromes; Diet; Electrophoresis, Polyacrylamide Gel; Enzyme Induction; Griseofulvin; Hyperplasia; Liver; Male; Mice; Microsomes, Liver; Mixed Function Oxygenases; NADH, NADPH Oxidoreductases; Oxidoreductases; Precancerous Conditions

Concentrations of hemopexin, a porphyrin-binding serum protein synthesized exclusively in the liver, increased significantly and concomitantly with levels of erythrocyte and liver protoporphyrin and coproporphyrin in mice made porphyric with 1% griseofulvin in the feed. Liver weights of porphyric mice increased remarkably. In comparison with controls, the ratio of the weight of normal to porphyric livers was at 10 days 1:2.1, at 21 days 1:2.8, and at 46 days 1:3.8. This increase in liver size was accompanied by increased cell division. The hepatic hyperplastic tissue fragments survived in vitro for several weeks and could be subcultured. The cultured cells, like those of the original liver, showed intense protoporphyrin fluorescence in the cytoplasm.

Topics: Animals; Coproporphyrins; Culture Techniques; Erythrocytes; Griseofulvin; Hemopexin; Hyperplasia; Liver; Mice; Organ Size; Porphyrias; Protoporphyrins

Topics: Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Griseofulvin; Hepatitis A; Hepatitis, Animal; Hepatomegaly; Hyperplasia; Hypertrophy; Liver Diseases; Mice; Research; Toxicology