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)

Parenchymal hepatocytes isolated from adult rats were cultured on three types of collagen-containing substrata: collagen-coated plates, collagen membranes and confluent diploid human fibroblasts. Hepatocytes on the latter two substrata maintained characteristic morphology for at least 10 days in culture, whereas degenerative changes (cell death and formation of multinucleated hepatocytes) and growth of nonparenchymal elements were seen after 5 days in cultures on collagen-coated plates. Parallel findings were seen on basal and induced levels of cytochrome P-450 and NADPH-cytochrome C reductase. The basal levels of cytochrome P-450 were not measurable after day 3 in hepatocytes cultured on collagen-coated plates, whereas measurable levels were maintained in the hepatocytes cultured on the other two substrata. Addition of phenobarbital or methylcholanthrene at day 5 in culture caused an increase in cytochromes P-450 and P-448, respectively, only in hepatocytes cultured on collagen membranes and confluent fibroblasts. Analogous results were seen for the enzyme NADPH-cytochrome C reductase. The similarities in performance between hepatocytes on collagen membranes and on human fibroblasts show that a continuous collagen-containing substratum is important for optimal performance of hepatocytes in primary culture. The possible importance of cultures of hepatocytes on human fibroblasts for carcinogenesis studies is discussed.
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PMID:Primary cultures of hepatocytes on human fibroblasts. 11 6

The ESR method was employed to study the distribution of the coordinative paramegnetic centers on the energy chain of electron transport and on the detoxifying system during carcinogenesis caused by a disturbance of the normal hormonal balance in the organism and at the tumour regression stage achieved with estrogen - in tumours of the ovary, spleen, liver and adrenals. At various stages of the hormonal carcinogenesis and under hormonal control both quantitative and qualitative changes on the paramagnetic centers were found. The tumour growth on liver and adrenals lowers the level of the catalytic form of the cytochrome P-450 and of the non-heme iron complexes. In metastases of ovarian tumours the kinetics of the triplet signal development is registered. In the tumour and on the liver an antibate change of the intensities of the signal was observed with g-factors of 2,1 and 2,15. At the tumour tissues a shift of the g-factor of free radicals was found - from g=2.005 to g=2.000. When a complete regression of tumours occured under hormonal balance control, the characteristics of the ESR spectra on the liver and adrenals restores to their values on intact tissues.
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PMID:[Coordinative paramagnetic enzyme centers during hormonal carcinogenesis and tumor regression under conditions of hormonal regulation]. 19 Oct 93

Vinyl carbamate was much more active (10 to 50 times) than ethyl carbamate for the initiation of skin tumors and for the induction of lung adenomas in mice. Vinyl carbamate was also mutagenic to Salmonella typhimurium TA 1535 and TA 100 in the presence of reduced nicotinamide adenine dinucleotide phosphate-fortified rat or mouse liver mitochondrial supernatant fractions. This mutagenic activity was inhibited strongly by cytochrome P-450 inhibitors. No mutagenic activity was observed for vinyl carbamate in the absence of added liver preparations or for ethyl carbamate in the presence or absence of liver fractions. Extensive tests with sensitive methods failed to detect vinyl carbamate as a metabolite of ethyl carbamate in the mouse in vivo. However, on administration of [ethyl-1-14C;1,2-3H]ethyl carbamate to adult mice the 3H/14C ratios of the hepatic DNA-, rRNA-, and protein-adducts were similar to each other and much lower than the ratio of the administered ethyl carbamate. These data are consistent with the presence of desaturated and/or oxidized ethyl groups in the macromolecular adducts. The qualitatively similar, but much stronger, carcinogenic activity of vinyl carbamate as compared to that of ethyl carbamate suggests that the metabolic pathways of these two carbamates may converge in the formation of similar or identical electrophilic reactants that bind covalently to macromolecules in vivo and initiate carcinogenesis.
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PMID:Vinyl carbamate as a promutagen and a more carcinogenic analog of ethyl carbamate. 35 28

Three topics are briefly reviewed relating to carcinogenesis of estrogen responsive tissues: (a) enzymology of benzo(a)pyrene activation by human tissues, (b) microsomal activation of estrogens to estrogen arene oxides and (c) estrogen and progesterone receptor studies in endometrial carcinoma. The following working hypothesis is stated on the etiology of gynecologic tumors: "Environmental chemicals, such as cigarette smoke, polycyclic and polyhalogenated hydrocarbons, etc., induce special forms of cytochrome P-450 monooxygenase and related enzyme systems which can activate endogenous or prescribed estrogens and non-steroid antiestrogens to act as initiators and/or promoters of neoplasia in estrogen-dependent organs." The role of estrogen receptors is perceived as a homing device or cellular "Trojan Horse" for these activated estrogens.
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PMID:Carcinogen activation by human uterine enzymes. 46 42

In vivo administration to rats of the mixed-function oxidase modifiers 3-methylcholanthrene (MC), pregnenolone-16 alpha-carbonitrile (PCN) or beta-naphthoflavnoe (beta-f) inhibits the hepatic microsome-catalyzed in vitro binding of dimethylnitrosamine (DMN) to DNA. This parallels their effect on DMN-demethylase I, regarded to be the sole activating step in DMN carcinogenesis and fails to account for the previously observed anomaly that MC and PCN inhibit, while beta-NF enhances, the hepatocarcinogenic activity of DMN. The in vitro binding of DMN is clearly dependent on microsomes and NADPH, and is strongly enhanced by soluble cytoplasmic proteins; the presence of the latter has no effect. however, on the relative response to pretreatment by the modifiers. In mice beta-NF enhances and PCN inhibits DMN-demethylase I; beta-NF has no effect on either the cytochrome P-450 level or on the LD50, while PCN strongly increases the cytochrome P-450 level but without influencing the LD50. Neither of the two modifiers has any effect in mice on the host-mediated mutagenicity of DMN in a dose-response study, except for the highest dose of DMN (200 mg/kg) where PCN pretreatment significantly enhanced mutagenicity. To account for the anomalous observations, other potential pathways of DMN metabolism have been explored. Whole rat liver nuclei or isolated nuclear membrane fractions contain no DMN-demethylase or diethylnitrosamine-deethylase activity. In a microsomal mixed-function amine-oxidase assay system neither purified enzyme preparations nor whole microsomes catalyze NADPH oxidation in the presence of DMN as substrate. In addition, the purified enzyme does not catalyze formaldehyde production in the DMN-demethylase assay system. Benzylamine, a typical inhibitor of mitochondrial monoamine oxidase (MAO), is a potent inhibitor of DMN-demethylase activity, but microsomes are devoid of MAO activity. Furthermore, purified MAO has no DMN-demethylase activity. The differential effect of modifiers on the carcinogenicity of DMN probably involves pathways other than DMN metabolism.
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PMID:Role of dimethylnitrosamine-demethylase in the metabolic activation of dimethylinitrosamine. 49 63

2-Acetylaminofluorene (AAF) was highly mutagenic to Salmonella typhimurium strain TA98, when activated by a liver post-mitochondrial supernatant fraction (S9 fraction) from guinea-pigs, in spite of the resistance of this species to AAF carcinogenesis and the low capacity of the liver of this species for N-hydroxylation of AAF. The mutagenicity was comparable to or higher than that resulting from activation by mouse- or rat-liver S9 fraction, and was not enchanced by treatment with cytochrome P-450 inducers, a combination of phenobarbital and 5,6-benzoflavone. In an attempt to understand this unexpected result we examined whether a cytochrome P-450 mixed-function oxidase system participated in the mutagenic activation of AAF by guinea-pig liver, as it does in the case of mouse liver. The mutagenic activation was: (1) completely dependent on the addition of a co-factor, NADPH, to the mutation assay system, (2) completely suppressed by antiserum against NADPH--cytochrome c reductase, and (3) sensitive to a cytochrome P-450 inhibitor, 7,8-benzoflavone. These results indicate that the cytochrome P-450 enzyme system is essentially involved even in the mutagenic activation of AAF by guinea-pig-liver S9 fraction. Based on both the present and other data, the mechanism of the mutagenic activation is discussed to explain the observed high mutagenic potential of AAF in the presence of guinea-pig-liver S9 fraction.
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PMID:Mutagenic activation of 2-acetylaminofluorene by guinea-pig liver homogenates: essential involvement of cytochrome P-450 mixed-function oxidases. 57 15

Under study was the effect of phenobarbital, medinal and aminazine on the development of lung tumors in mice, as well as on the content of cytochrome P-450 in rat liver microsomes. Phenobarbital and medinal administration resulted in a 2-8 fold increase in cytochrome P-450 amount. Aminazine would reduce the latter but insignificantly. The number of urethan induced lung adenomas in mice was reduced by 64 per cent in phenobarbital exposure while medinal yielded only the decrease by 25-44 per cent. Aminazine failed to effect urethan carcinogenesis. Medinal would also suppress the development of DMBA induced lung tumors in mice by 34 per cent, but MC-by 50 per cent.
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PMID:[The relationship between the activity of microsomal enzymes and pulmonary carcinogenesis in mice]. 82 74

This work confirms the previous observation that a single application of N-hydroxy-2-fluorenylacetamide or N-hydroxy-3-fluorenylacetamide to the mammary gland of the rat induced a high incidence of tumors, whereas the corresponding arylamides, N-2-fluorenylacetamide (2-FAA) and N-3-fluorenylacetamide, were only weakly active. The results suggested N-hydroxylation of the arylamides as a prerequisite for mammary carcinogenesis. Since N-hydroxylation of 2-FAA by hepatic microsomes is catalyzed by the mixed-function oxidase containing cytochrome P-450 or the 2-methylcholanthrene-inducible cytochrome P1-450, we examined whether these cytochromes are present in mammary microsomes. In contrast to liver, neither cytochrome nor N-hydroxylation of 2-FAA was detected in the mammary gland of normal and 3-methylcholanthrene-treated rats. These experiments indicated that the N-hydroxylation of 2-FAA, although obligatory for induction of mammary neoplasia, is not performed in the mammary gland but may take place in the liver. We also examined the carcinogenicity of N-acetoxy-2-fluorenylacetamide and N-acetoxy-3-fluorenylacetamide for the mammary gland upon topical application. Since both acetates were carcinogenic and since the acetyl group of acetyl coenzyme A is transferred to fluorenylhydroxamic acids at pH 7.4, these esters may be ultimate carciogens in mammary carcinogenesis. Ovariectomized rats did not develop mammary tumors after a single application of the fluorenylhydroxamic acids, and administration of estradiol and fluorenylhydroxamic acids to the ovariectomized rats did not improve the tumor yield. These results indicate that induction of mammary tumors by fluorenylhydroxamic acids is under hormonal control.
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PMID:Mammary carcinogenesis in the rat by topical application of fluorenylhydroxamic acids and their acetates. 83 Apr

The capacity of isolate mouse liver microsomes to alter the mutagenicity for bacteria of the primary carcinogen N-methyl-N'-nitro-N-nitrosoguanisine (MNNG) and the secondary one dimethylnitrosamine (DMN) was studied. Microsomal activation of DMN and inactivation of MNNG were decreased by protein- and protein-cholinedeficient diets and were increased by pretreatment with microsomal enzyme inducers. The decrease and increase paralleled the content of cytochrome P-450 present in the different microsomal preparations. With human liver microsomes of differing cytochrome P-450 contents similar correlation was obtained, whereas normal rat liver microsomes did not activate or inactivate DMN or MNNG. Oxidative demethylation of DMN by mouse liver microsomes and the activation of DMN to a mutagen followed similar kinetics. Both reactions were inhibited by carbon monoxide and the inhibition was maximally reversed by monochromatic light at 450 nm. These observations indicate that at least some carcinogens are activated or inactivated by the unspecific cytochrome P-450 dependent enzyme system, suggesting that the extent of this biotransformation may be one factor influencing human carcinogenesis.
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PMID:Cytochrome P-450 in the activation and inactivation of carcinogens. 115 49

Studies with 58 polynuclear aromatic hydrocarbons have shown that to repress demethylation of dimethylnitrosamine (DMN) in rat liver, the hydrocarbons must satisfy specific requirements of molecular geometry regarding size, shape, and coplanarity. Expressing the molecular size of these planar compounds by the two-dimensional area occupied, the size for maximal repressor activity ranges between about 85 and 150 A2. In addition to being within the correct molecular size range the hydrocarbons must have an elongated-rather than compact-molecular shape; circularly shaped and/or highly symmetrical hydrocarbons, such as coronene, triphenylene, ovalene, and tetrabenzonaphthalene, have very low activity or are inactive, in spite of being in the optimum size range. Coplanarity of the molecule is a critical requirement; thus, the potent carcinogen, 9,10-dimethyl-1,2-benzanthracene, is inactive as repressor of DMN-demethylase synthesis. Two exceptions, fluoranthene and benzol[ghi] fluoranthene, showed significant induction of DMN-demethylase. The molecular size distribution of hydrocarbons that repress the DMN-demethylase shows a mirror-image relationship with respect to the earlier reported molecular size requirement for indcution of azo dye N-demethylase. Compounds other than hydrocarbons also show the mirror-image relationship in the sense that pregnenolene-16alpha-carbonitrile, alpha- and beta-naphthoflavone, and Aroclor 1254 (known to be inducers of various mixed-function oxidases) are strong repressors of DMN-demethylase. Aminoacetonitrile, a strong inhibitor of carcinogenesis by DMN, is also a potent repressor of DMN-demethylase. The enzyme is inhibited by pretreatment of the animals with cobaltous chloride, an inhibitor of the synthesis of cytochrome P-450. Pregnenolone-16alpha-carbonitrile and 3-methylcholanthrene, despite their similarity of action on DMN-demethylase, have different effects on azo reductase, which is repressed by the former and induced by the latter compound.
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PMID:Dimethylnitrosamine-demethylase: molecular size-dependence of repression by polynuclear hydrocarbons. Nonhydrocarbon repressors. 124 85


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