griseofulvin and Liver-Neoplasms

Mallory's body filament assembly includes polypeptides of the cytokeratin class of intermediate filaments and also higher molecular weight polypeptides normally found only in the cytokeratins of mature keratinocytes of the epidermis. These additional polypeptides may alter both the morphologic characteristics and increase the resistance to dissolution of the filaments by Ca++-activated protease activity. Thus, it is likely that the kinetics of Mallory's body filament assembly and dissolution favor growth of the filaments. In rodents fed certain carcinogens, Mallory's body formation has been accompanied by the induction of the oncofetoenzyme gamma-glutamyl transpeptidase (GGT), suggesting that Mallory's body formation, like GGT induction, is a phenotypic change related to the process of neoplastic transformation in rodents.

Topics: Animals; Carcinogens; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cytoskeleton; gamma-Glutamyltransferase; Griseofulvin; Humans; Intermediate Filament Proteins; Keratins; Liver; Liver Diseases; Liver Neoplasms; Liver Neoplasms, Experimental; Lung; Lung Diseases; Phosphorylation; Protein Precursors

Topics: Animals; Carcinogens; Carcinoma, Hepatocellular; Cell Line; Chromosome Aberrations; Chromosomes; Drug Evaluation, Preclinical; Female; Griseofulvin; Humans; Liver; Liver Neoplasms; Mice; Necrosis; Pregnancy; Rats; Teratogens

Mice primed by feeding griseofulvin or diethyl 1,4-dihydro 1,4,6-trimethyl 3,5-pyridine decarboxylate for 5 months followed by drug withdrawal for 1 month (drug-primed mice) were given thioacetamide intraperitoneally, and the livers were subsequently studied at intervals up to 7 days. The hepatocellular proliferative response was measured by immunostaining for proliferative cell nuclear antigen. Necrosis was followed by measuring ALT. Mallory bodies were identified by immunoperoxidase stains for ubiquitin and cytokeratin. Preneoplastic foci were localized using immunofluorescence stain for glutathione S-transferase (GST mu) and histochemical stain for gamma glutamyl transpeptidase (GGT). The results showed that the preneoplastic foci selectively proliferated and expanded and formed nodules as indicated by quantitation of nuclei stained positive for proliferating cell nuclear antigen after thioacetamide treatment. Data support the hypothesis that the preneoplastic foci consisted of clones of hepatocytes which preferentially express GST mu, GGT and Mallory bodies. These preneoplastic cells selectively proliferate in response to the promoter effects of necrosis-induced liver cell regeneration ("chemical partial hepatectomy").

Topics: Animals; Carcinoma, Hepatocellular; gamma-Glutamyltransferase; Glutathione Transferase; Griseofulvin; Hepatocytes; Liver; Liver Neoplasms; Liver Regeneration; Mice; Precancerous Conditions; Pyridines; Thioacetamide

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

Rhodamine B staining in conjunction with fluorescence microscopy is shown to demonstrate Mallory bodies. Mallory body morphology, localization, and distribution in hepatocytes from griseofulvin-fed mice, human hepatoma, and human alcoholics were similar to those observed in the same tissues after conventional staining methods for Mallory bodies. The presence of these inclusions was further confirmed by specific cytochemical localization with indirect immunoperoxidase labeling, horseradish peroxidase labeling, and electron microscopy. Other tinctorial or histochemical procedures previously used for keratin or prekeratin (modified Mallory stain, Kreyberg method, Pauly method for histidine) also stained Mallory bodies for study with white light microscopy but with decreasing sensitivity respectively. Mallory bodies from mouse and human liver both appear to contain a keratin-like moiety. This entity may be simply, rapidly, and permanently stained with rhodamine B, and selectively and reproducibly demonstrated with fluorescence microscopy.

Topics: Animals; Carcinoma, Hepatocellular; Endoplasmic Reticulum; Griseofulvin; Humans; Keratins; Liver; Liver Diseases, Alcoholic; Liver Neoplasms; Mice; Microscopy, Fluorescence; Rhodamines; Staining and Labeling; Xanthenes

Treatment of mice with griseofulvin for 8 months induced hepatocellular nodules in the liver which persist after discontinuation of griseofulvin feeding. We investigated the porphyrogenic effect of griseofulvin on these nodules and surrounding nonneoplastic liver after renewed short-term exposure of tumor-bearing mice to this agent. Griseofulvin treatment for 4 days led to marked elevation of the activity of 5-aminolevulinate synthase in peritumoral (3.8-fold) and control (6-fold) liver. The increase in enzyme activity was much less pronounced in the nodules (1.5-fold). Ferrochelatase activity was markedly decreased under the same experimental conditions in both peritumoral and control livers (to 18 and 13.5%, respectively, of the pretreatment values), but the effect was considerably smaller in nodules (to 40% of the pretreatment value). These results may explain the lack of porphyrin accumulation in tumor tissue.

Topics: 5-Aminolevulinate Synthetase; Animals; Diet; Ferrochelatase; Griseofulvin; Heme; Hemin; Liver; Liver Neoplasms; Lyases; Male; Mice; Neoplasms, Experimental; Porphyrias; Protoporphyrins

Topics: 5-Aminolevulinate Synthetase; Animals; Carcinoma, Hepatocellular; Ferrochelatase; Griseofulvin; Liver Neoplasms; Mice; Neoplasms, Experimental; Porphyrias; Protoporphyrins

Griseofulvin (GF) feeding of mice resulted in protoporphyria, liver cell damage, bile duct alterations, and finally hepatoma formation. In addition, hepatocellular hyalin developed, resembling in its morphology classic Mallory bodies (MB) as seen in alcoholic and nonalcoholic liver disorders in man. Liver cells containing MB often displayed features of severe cell damage and MB were finally released into the sinusoids and degraded by macrophages. The rapid disappearance of MB following GF discontinuation and the reappearance after resumption of GF feeding suggest an intimate relationship between metabolic alterations in the hepatocytes exerted by the drug and MB formation. This assumption is further supported by the fact that MB change their tinctoreal properties in chromotrope aniline blue-stained sections after GF discontinuation, possibly relfecting degeneration. Long term GF treatment apparently primed the liver for MB formation since the cells were able to respond almost instantly with MB to a GF challenge after a 1-month GF-free period.

Topics: Animals; Bile Ducts; Carcinoma, Hepatocellular; Endoplasmic Reticulum; Griseofulvin; Hyalin; Liver; Liver Neoplasms; Mice; Porphyrias

Topics: Animals; Animals, Newborn; Carcinogens; Carcinoma, Hepatocellular; Female; Griseofulvin; Infusions, Parenteral; Liver Neoplasms; Male; Mice; Neoplasms, Experimental

Topics: Animals; Griseofulvin; Liver Neoplasms; Male; p-Dimethylaminoazobenzene; Rats

Topics: Animals; Chemical and Drug Induced Liver Injury; Female; Griseofulvin; Hepatomegaly; Liver; Liver Neoplasms; Male; Mice; Porphyrins