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)

Transferrin binding was found to be around 60-fold higher in hepatocyte nodules compared to normal liver, with no apparent differences in binding affinity or molecular weight of binding proteins, indicating that the increase in [125I]transferrin binding was the result of an increased number of binding sites with similar properties as in normal liver. The relative 'induction' of transferrin receptors was most marked in the total membrane fraction followed by membrane subfractions comprising endoplasmic reticulum, the Golgi complex and endocytic vesicles. Despite the increased number of transferrin receptors, the in vivo endocytosis of transferrin, measured as uptake of [125I]ferrotransferrin, was quantitatively similar in nodular cells compared to normal liver. The number of transferrin receptors in regenerating liver, 48 h after partial hepatectomy, was increased 20-fold over normal levels, but binding affinity, receptor structure and kinetics of transferrin uptake were normal. A slower than normal rate of 59Fe accumulation in hepatocyte nodules may suggest an alteration in the dissociation of iron from ferrotransferrin, thereby suggesting one mechanism relevant to the iron storage deficiency in nodular cells.
Carcinogenesis 1986 Sep
PMID:The transferrin receptor in hepatocyte nodules: binding properties, subcellular distribution and endocytosis. 301 98

A new method has been developed for the quantitative analysis of an ultrastructural change in hepatocyte rough endoplasmic reticulum (ER) that is induced by liver carcinogens. Hitherto only subjective observations of this alteration had been made. Male inbred Leeds rats were fed a diet containing 0.06% of the carcinogenic azo dye 3'-methyl-4-dimethyl-aminoazobenzene (3'MeDAB). Groups of treated rats, together with untreated controls, were sacrificed after 10 days, 4 weeks, 10 weeks and 17 weeks. Samples of liver tissue from each animal and from 10 3'MeDAB-induced hepatocellular carcinomas (HCC), were examined by electron microscopy. A quantitative study was carried out to investigate the effect of chronic exposure to 3'MeDAB upon the state of aggregation of the hepatocyte rough ER into parallel arrays. As early as 10 days after the start of treatment, the rough ER showed a highly significant degree of disaggregation: the mean number of ER cisternae per array fell from the control value of 6.20 to 3.73. This change was sustained throughout the experiment. At 17 weeks, comparison of the mean array size in the HCC cells with that in the surrounding hepatocytes revealed a further significant decline, from 3.46 to 2.12. Further groups of rats were fed other azo dyes for 4 weeks and subjected to the same assay. The carcinogens 4'-methyl-4-dimethylaminoazobenzene (4'MeDAB) and N,N-dimethyl-4-amino-N-acetyl-N-monomethyl-4-aminoazobenzene (DAAMAB) resembled 3'MeDAB with respect to the degree of rough ER disaggregation they induced. In contrast, the non-carcinogen 3'-trifluoromethyl-4-dimethylaminoazobenzene (3'TFMeDAB) had no such effect, while the weak initiator 2-methyl-4-dimethylaminoazobenzene (2MeDAB) induced disaggregation to a lesser degree than the strong carcinogens. At least with the azo dyes used in this study, the extent of rough ER disaggregation appears to be related to hepatocarcinogenesis.
Carcinogenesis 1988 Jun
PMID:Quantitative electron microscopy of carcinogen-induced alterations in hepatocyte rough endoplasmic reticulum. I. Chronic effect of 3'MeDAB and short-term effects of azo dyes of different carcinogenic potentials. 313 Oct 35

Most drugs and xenobiotics are lipid-soluble compounds that need to be transformed into more polar water-soluble molecules by a system of hepatic monoxygenases in order to be excreted by the kidney and the liver. This system is also called cytochrome P-450. It is found in animals, as well as plants. It is located in the cellular endoplasmic reticulum of numerous tissues, but it is most active in the liver. It is made up of several isoenzymes differing from one another by the structure of their apoproteins, their immunological characteristics and their affinity for various substrates. Cytochrome P-450 has great variability, being influenced by exogenous factors (drug intake, ionizing radiation, stress, diet) and individual endogenous factors (age, sex, genetic factors). Several non specific tests exploring the system are available. They include: direct investigations carried out on liver biopsies, which are seldom used in clinical practice, and indirect investigations, such as the measurement of the clearance of exogenous substances, of urinary metabolites of endogenous substances and of specific enzymes. Induction and inhibition of microsomal activity are of the utmost interest to the clinician in various fields such as toxicology, carcinogenesis, drug interactions or drug habituation, metabolic regulations and maintenance of body homeostasis. Seven classes of enzyme inducers have been defined, but the exact mechanism of this has only been identified for two of them (the barbiturate and polycyclic hydrocarbon groups). Several drugs have been identified as enzyme inhibitors, the best known to the anaesthesiologist being macrolide antibiotics, imidazole derivatives, cimetidine, chloramphenicol and isonazide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hepatic mono-oxygenases]. 336 13

The effect of carcinogenesis on various hepatic microsomal parameters and related cell functions was studied in two tumor models. Hepatocarcinoma was produced by diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF) (Solt-Farber model) and mammary adenocarcinoma using R3230 AC cancer cell line. In these models the effect of the tumor on metabolic functions of hepatocytes was studied. In the DEN/2AAF tumor model in nodules phase I components (cytochrome P-450, aminopyrine N-demethylase, arylhydrocarbon hydroxylase) were reduced, together with microsomal progesterone content and total and specific progesterone binding. Phase II components (glutathione, glutathione S-acyltransferase, UDP-glucuronyl transferase, epoxide hydrolase) were increased. In hepatoma the effects were more enhanced. Nodules grown in the speen retained the dedifferentiated enzyme characteristics. In the R3230 AC mammary adenocarcinoma phase I components of the hepatic endoplasmic reticulum were reduced, and phase II components increased. Progesterone content and receptor binding were also increased. These results indicate that enzymatic abnormalities in the liver cell are connected with cancer production and the hepatic dedifferentiation seems to be indistinguishable in tumor-bearing liver from those seen with extrahepatic neoplasms.
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PMID:Hepatic metabolism and carcinogenesis. Its role in hepatoma and adenocarcinoma. 338 80

In our studies on activation of the Clara cell by biological substances and its relationship to pulmonary carcinogenesis, we found that large doses of glycerol induced drastic morphologic changes selectively in the Clara cell among distal airway epithelial cells in ddY mice. Subcutaneous injection of glycerol (7.2 g/Kg body weight) caused cytoplasmic edema with disruption of endoplasmic reticulum membranes at 1 and 3 hours, followed by hyperplasia of smooth endoplasmic reticulum (SER) at 12 and 24 hours. Concentric lamination of SER was observed at 48 and 96 hours. Oral administration of 5% glycerol in drinking water for 2 to 8 weeks induced more conspicuous hyperplasia and hypertrophy of SER in the Clara cells. Electron microscopic morphometry revealed a 3-fold increase in the profile area of SER in the Clara cells of the animals at 2 and 8 weeks. Both the profile area and the number of secretory granules increased significantly at 2 and 8 weeks, and those of mitochondria tended to increase with time of glycerol treatment. In both experiments, the mitochondria of the Clara cells exhibited marked elongation and distortion of the contour associated with appearance of prominent cristae. These results suggest that large doses of glycerol induce marked alteration in the functional activity of the mouse Clara cell.
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PMID:Morphologic alteration of mouse Clara cells induced by glycerol: ultrastructural and morphometric studies. 358 82

The fluorescent 12-O-tetradecanoylphorbol-13-acetate (TPA) analogue dansyl-TPA allowed the distribution of fluorescent molecules to be visualized in living mouse fibroblasts. The entry of dansyl-TPA into cells occurred within millisecond time scale and was found largely energy independent. Dansyl-TPA was shown to stain the endoplasmic reticulum, Golgi apparatus, mitochondria and nuclear membrane. In addition, dansyl-TPA fluorescence was found to parallel that obtained with rhodamine-conjugated anti-alpha tubulin. The intracellular location of the dansyl-TPA fluorescence can be taken into account to explain the pleiotropic action of TPA in the cells.
Carcinogenesis 1985 Mar
PMID:Intracellular localization of 12-O-3-N-dansylamino TPA in C3H/10T1/2 mouse cell line. 383

Mammals have at least two epoxide hydrolases (EHs) with a broad significance in drug metabolism. One enzyme is localized in the endoplasmic reticulum and other membranes (EHm), and the other is in the cytosol (EHc). In the present study we found that humans differ greatly in the activities of these enzymes in liver. The specific activities in microsomes from 166 subjects (most of them patients suffering from hepatic diseases), measured with benzo[a]pyrene 4,5-oxide as the substrate, varied by a factor of 63. The activities in the cytosol, determined with trans-stilbene oxide as substrate varied 539-fold among 135 subjects. A subdivision into different diagnostic groups showed an increase in EHm activity (1.7-fold control) but not EHc activity in tuberculosis patients treated with rifampicin, ethambutol and isoniazid. No other diagnostic group showed significantly altered EH activities. Furthermore the activities did not differ between females and males, alcoholics and non-alcoholics or smokers and non-smokers. In the 77 subjects where both EHc and EHm activities were determined, no correlation between them was observed, indicating separate biological control.
Carcinogenesis 1985 Feb
PMID:Interindividual variations in the activities of cytosolic and microsomal epoxide hydrolase in human liver. 397 88

1. Changes in the structure and function of the rough-surfaced endoplasmic reticulum of the rat liver as deduced by electron microscopy, polysome analysis and the amino acid-incorporating activity of microsome fractions have been followed at various time-intervals after a single intraperitoneal dose of the hepatocarcinogen 4-dimethylaminoazobenzene. 2. The earliest effect observed was detachment of polysomes and disorganization and vesiculation of the cisternae of the rough-surfaced endoplasmic reticulum. This occurred after 6hr. 3. Subsequent to this was a phase of polysome disaggregation accompanied by impaired amino acid-incorporating activity by microsomes together with a much enhanced stimulating effect of polyuridylic acid on amino acid uptake. This reached a maximum at 24hr. 4. By 40hr. polysomes had re-formed and the amino acid-incorporating activity, together with the polyuridylic acid effect, were similar to those in controls. 5. It was not until 112hr. that something like the normal structure of the rough-surfaced endoplasmic reticulum was re-established. 6. It is not yet possible to relate these changes specifically with the process of azo-dye carcinogenesis.
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PMID:The effect of a single intraperitoneal dose of the hepatocarcinogen 4-dimethylaminoazobenzene on the rough-surfaced endoplasmic reticulum of the liver of the rat. 496 58

Azoxymethane (AOM) induced mucinous colloid adenocarcinomas of the colon have been studied by light microscopy, histochemistry and transmission electron microscopy. This neoplasm constituted 2.6% of the induced carcinomas. Histogenetically they were formed directly from the flat mucosa without going through a benign polyp-cancer sequence. By light microscopy, the neoplasms were characterized by lakes of abundant extracellular mucin within which were cells often distended with intracellular mucin. Histochemically, this mucin was composed of a mixture of neutral and acidic mucopolysaccharide, the latter being predominantly sialomucin. Ultrastructurally, the cells exhibited a mixed differentiation. The majority of the cells were hyperdistended with mucin, resembling the goblet cells. Other cells contained abundant rough endoplasmic reticulum, free polysomes and very little intracellular mucin. There were a few endocrine cells as well as mucous cells with dense core granules. It seems that similar to the normal colon, the neoplastic colon also contains cells at various stages of differentiation. A hypothesis to explain these events in colon carcinogenesis is proposed.
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PMID:Mucinous colloid adenocarcinoma of colon in Fischer-344 rats. Light microscopy, histochemistry and ultrastructure. 609 44

Chlordecone (Kepone) is a decachloroketone analog of the dodecachlorohydrocarbon mirex and is used as a stomach poison insecticide. Despite the structural similarity to mirex, chlordecone is unlike mirex in general organ-specific toxic properties. Chlordecone is primarily accumulated in the liver, where it causes a variety of morphological and biochemical alterations. Although less effective than mirex as a hepatotoxin, it causes liver enlargement, focal necrosis, mitochondrial changes, fatty infiltration of hepatocytes, and proliferation of endoplasmic reticulum. Chlordecone accumulation and morphological alterations in the liver were also observed in occupationally exposed human patients. Induction of hepatic microsomal mixed-function oxidases (MFOs) and impaired production and utilization of hepatocellular energy are the principal biochemical aberrations produced by chlordecone. Chronic exposure causes carcinogenesis in mice and rats. Hyperplastic nodules, which progress to hepatocellular carcinomas, are the principal pathological lesions. Acute and chronic exposures to chlordecone result in hepatobiliary dysfunction manifested as impaired excretion of anionic compounds accompanied by choleresis. Exposure to chlordecone results of greatly potentiated haloalkane hepatotoxicity, representing a most potent toxic interaction at otherwise individually nontoxic levels. In view of the demonstrated carcinogenic effect of chlordecone, such interactions at very low levels assume extraordinary significance in terms of chronic toxicological and pathological manifestations induced by combinations of toxic chemicals.
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PMID:Chlordecone-induced hepatic dysfunction. 617 67


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