Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of single doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (10 micrograms/kg) increased estradiol 2-hydroxylase (E2OHase) activity approximately 2-fold in liver microsomes of female rats but had no effect on E2OHase activity in hepatic microsomes of male rats. In contrast, TCDD increased P-450d (an enzyme which has a high turnover number for E2OHase in a reconstituted enzyme system) 10- to 20-fold in livers of both male and female rats. The discrepancy between the increases in P-450d and E2OHase activity in liver microsomes of TCDD-induced rats was abolished by the addition of exogenous purified P-450 reductase to the microsomal assays for E2OHase, suggesting that reductase was limiting in the in vitro assays. When E2OHase activity was assayed in the presence of exogenous reductase, TCDD increased E2OHase 2-fold and 4-fold respectively in liver microsomes of male and female rates. Antibody to P-450d completely inhibited the increase in E2OHase activity in liver microsomes of TCDD-treated male and female rats, but had little effect on E2OHase activity in liver microsomes of untreated male or female rats. These data indicate that P-450d is responsible for the increase in E2OHase activity in TCDD-treated rats, but other P-450 isozymes are responsible for constitutive E2OHase activity. Biweekly administration of 1.4 micrograms/kg of TCDD for 30 weeks as a potential promoter of hepatocarcinogenesis increased the volume of the liver occupied by gamma-glutamyl transpeptidase (GGT)-positive foci in livers of female rats given a necrogenic dose of diethylnitrosamine (DEN) (200 mg/kg) as the initiator. Biweekly doses of 0.14-1.4 micrograms/kg TCDD in this model also increased P-450d (7-fold) and E2OHase activity maximally (4-fold) in DEN-initiated rats. Moreover, initiation with DEN substantially enhanced the effects of the low dose of TCDD on both hepatic microsomal P-450d and E2OHase activity.
Carcinogenesis 1988 Nov
PMID:Increases in cytochrome P-450 mediated 17 beta-estradiol 2-hydroxylase activity in rat liver microsomes after both acute administration and subchronic administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin in a two-stage hepatocarcinogenesis model. 314 Oct 74

The effect of the monoclonal antibody MAb 2-66-3, directed against the major rat liver phenobarbital (PB)-induced cytochrome P-450 (P-450), on the S9-mediated mutagenicity of N-nitrosodimethylamine (DMN) in Salmonella typhimurium strain TA1530 was studied using liver S9 from PB-treated mice. This MAb enhanced approximately 2-fold S9-mediated mutagenicity of DMN but inhibited both its N-demethylation and N-denitrosation by 50%. Thus MAb-mediated enhancement of DMN mutagenesis does not result from altered activation/inactivation pathways, both known to involve P-450 isozymes. DMSO, a hydroxyl radical (HO.) scavenger and desferrioxamine, an inhibitor of HO.-dependent reactions, quenched the MAb-mediated enhancement of DMN mutagenesis, implicating the HO.-dependent activation of DMN to mutagenic species. As a mechanism, we propose that the binding of this MAb to P-450 isozyme implicated in DMN metabolism decreases the functional coupling between the reductase and the P-450 complex, leading to an increased electron flow from the reductase towards molecular oxygen to form reduced oxygen species (HO.) at the expense of the monooxygenase functions.
Carcinogenesis 1987 Dec
PMID:A monoclonal antibody against cytochrome P-450 enhances mutagen activation of N-nitrosodimethylamine by mouse liver S9: studies on the mode of action. 331 87

Synthesis of 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline (N-hydroxy-IQ), a reactive metabolite of 2-amino-3-methylimidazolo[4,5-f]quinoline (IQ), was achieved by a modification of an earlier method. N-Hydroxy-IQ was purified by a two-step procedure involving C18 Sep-Pack and semi-preparative h.p.l.c. Additional h.p.l.c. methods were developed to monitor the synthesis of N-hydroxy-IQ, and to measure IQ and other IQ derivatives on the same h.p.l.c. profile. The structure of N-hydroxy-IQ was confirmed by mass spectral analysis following derivatization to azoxy-IQ, phenyl-azoxy-IQ and acetoxy-acetamido-IQ, and by chemical reactivity studies. Mutagenicity studies with the nitro-reductase-deficient strain of Salmonella TA98 showed that N-hydroxy-IQ is directly mutagenic, having a specific activity of 2 X 10(4) revertants/nmol. The data confirm that N-hydroxy-IQ is a mutagenic metabolite of IQ and further implicate the hydroxylamine in the carcinogenicity of IQ.
Carcinogenesis 1987 Jul
PMID:Synthesis, purification and mutagenicity of 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline. 359 19

Water solubility and non-toxic properties of ascorbic acid are taken as criteria for beneficial effects of large doses of the vitamin. In the present study, male guinea pigs, dosed daily with 15, 30 or 50 mg/100g body weight for 10 weeks, demonstrated no differences in effect on liver and lung weights, body growth and microsomal protein contents of liver and lung when compared with controls. When guinea pigs were fed excessive ascorbic acid, there was a small non-significant increase (p less than 0.05) in hepatic and pulmonary cytochrome P-450, and significant increase (p less than 0.05) in hepatic cytochrome b5 which was accompanied with a significant increase in arylhydrocarbon hydroxylase activity in the two organs. Activity of NADPH-dependent cytochrome c-reductase was decreased in liver and remained unaffected in lung and colon. Drug detoxifying enzymes responded in different ways to increased intake of ascorbic acid. Activity of UDP-glucuronyltransferase remained unchanged on feeding excessive ascorbic acid, whereas glutathione S-transferase was decreased significantly in liver and was unaltered in lung and colon. Reduced glutathione was decreased only in the lung. The observed changes in drug activating and detoxifying enzymes appear to be important from drug pharmacokinetics and carcinogenesis point of view.
 ...
PMID:Effect of large doses of ascorbic acid on the hepatic and extra-hepatic drug-metabolizing enzymes in guinea pig. 380 Oct 39

The effect of zinc acetate on the mutagenicity of 1-nitropyrene (1-NP) in Salmonella typhimurium TA100 was examined. By the pre-treatment of the cells with zinc ions (0.24 mM) the revertant colonies caused by 1.5 microM of 1-NP in the pre-incubation mixtures increased approximately 3-fold, while the survival colonies decreased to approximately 75% under the same conditions. The enhancing effect of zinc ions on the mutagenicity was not dependent on the increase of 1-NP incorporation into the cells. The addition of zinc ions to whole cell preparations had no enhancing effect on the 1-NP reductase activity. The effect of zinc acetate on the binding of [3H]1-NP to DNA in S. typhimurium TA100 was examined. The amount of [3H]1-NP bound to DNA increased by the pre-treatment of the cells with zinc ions. A good correlation was found between the extent of binding of 1-NP to DNA and the frequency of induced histidine reversions in the cells treated with zinc ions under the experimental conditions used.
Carcinogenesis 1985 Jan
PMID:Enhancement of DNA binding and mutagenicity of 1-nitropyrene by zinc acetate in Salmonella typhimurium TA100. 388 Nov 97

N-acetylcysteine (NAC) was administered to rats in various combinations with an enzyme inducer (Aroclor 1254) and with depletors of reduced glutathione (GSH), i.e., diethyl maleate (DEM) and buthionine sulfoximine (BSO). NAC increased intracellular glutathione levels in erythrocytes and in liver and lung cells, and replenished its stores following depletion. It did not affect the concentrations nor the spectral properties of cytochromes P-450 in hepatic and pulmonary microsomes, whereas it stimulated, especially in Aroclor-pre-treated animals, cytosolic enzyme activities involved in NADP reduction (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase), in glutathione reduction (GSSG-reductase) and in the reductive detoxication of xenobiotics by-passing formation of reactive oxygen species (DT-diaphorase). In vivo treatment with the drug enhanced detoxication by liver and lung S-12 fractions of direct-acting mutagens (ICR 191, epichlorohydrin, 4-nitroquinolino-N-oxide and dichromate) and counteracted opposite effects triggered by administration of GSH depletors. The metabolic activation of procarcinogens (aflatoxin B1, 2-aminofluorene, cyclophosphamide, benzo[a]pyrene, a tryptophan pyrolysate product and cigarette smoke condensate) was inhibited by NAC in uninduced rats, while it was further stimulated in Aroclor-pre-treated animals. Additional assays, performed also with other enzyme inducers (phenobarbital and 3-methylcholanthrene) suggested that the effect of NAC on the metabolic activation of procarcinogens depends on the balance between an increased production of mutagenic metabolites (prevailing in induced animals) and their binding by intracellular thiols (prevailing under normal conditions). Thus, due to its dual role as a nucleophile and as a SH donor, NAC appears to exert protective effects by modulating glutathione metabolism and the biotransformation of mutagenic/carcinogenic compounds. This may have clinical relevance, since NAC is administered to individuals, such as cigarette smokers, who are more heavily exposed to GSH depletors and to carcinogenic agents.
Carcinogenesis 1985 Dec
PMID:In vivo effects of N-acetylcysteine on glutathione metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds. 390 42

Nitrosamine-induced hepatocarcinogenesis has been used to investigate the regulation and expression of different drug-metabolizing enzymes in preneoplastic and neoplastic lesions in the female Wistar rat. The enzymes investigated were two phenobarbital-inducible cytochrome P-450 (cyt. P-450) isoenzymes (PB1 and PB2, mol. wt. 52 000 and 53 500, respectively), two 3-methylcholanthrene-inducible forms (MC1 and MC2, mol. wt. 54 500 and 57 000, respectively), NADPH-cytochrome P-450 reductase, the cytosolic glutathione transferases (GSTs) B and C and the microsomal epoxide hydrolase with broad substrate specificity (mEHb). Carcinogen-induced lesions were identified by use of the known markers of hepatocarcinogenesis adenosinetriphosphatase and gamma-glutamyl transpeptidase. While the GSTs and mEHb were increased in all preneoplastic and neoplastic lesions, the levels of the individual cyt. P-450 isoenzymes were characteristically different from each other. In many of the early ATPase deficient islets PB1 was elevated, whereas the content of the other cyt. P-450 forms and NADPH-cytochrome P-450 reductase was either unchanged or slightly lowered. At later stages of hepatocarcinogenesis PB1 returned to the levels of the surrounding tissue, while the other cyt. P-450 isoenzymes were decreased, the most prominent reduction being found in MC1. In neoplastic nodules all the cyt. P-450s and NADPH-cyt. P-450 reductase were diminished, some of them dramatically. These findings indicate that in spite of a common response of groups of P-450s to inducing agents, individual P-450 isoenzymes are also regulated separately. Moreover, the constant elevation of mEHb and GSTs in all lesions investigated in this study demonstrates that these enzymes, which are largely involved in deactivation, are regulated in a different fashion from the predominantly carcinogen-activating monooxygenases. The observed differences in enzyme pattern may provide a useful method for subdividing and categorizing preneoplastic and neoplastic lesions.
Carcinogenesis 1985 Apr
PMID:Regulation and expression of four cytochrome P-450 isoenzymes, NADPH-cytochrome P-450 reductase, the glutathione transferases B and C and microsomal epoxide hydrolase in preneoplastic and neoplastic lesions in rat liver. 392 Dec 70

A benzo[a]pyrene (B[a]P) hydroxylase activity and epoxide hydrolase (EH) activity have been found in rat liver nucleoli obtained from untreated (C) and 3-methylcholanthrene (3-MC) pretreated rats. A comparison of the enzyme activities was made in rat nuclei and nucleoli. Light and electron microscopic observations of nucleolar preparations did not reveal significant contamination either by intact nuclei or by nuclear membranes, and glucose 6-phosphatase, a marker of microsomal activity, was not detected in our nucleolar preparations. NADPH cytochrome c-reductase could be measured in C and 3-MC nuclei and very low but detectable activity was found in the nucleoli. Nucleolar preparations revealed significant hydroxylating activity, which was inducible by 3-MC in nuclei but not in nucleoli. The presence of EH in nucleoli was demonstrated with phenanthrene 9,10-oxide and B[a]P 4,5-oxide, but the nucleolar activities were lower than those obtained using intact nuclei. The addition of 1,1,1-trichloropropene 2,3-oxide completely inhibited EH activity. Furthermore the presence of covalently-bound metabolites of B[a]P formed in isolated nucleoli was demonstrated by cytofluoromicroscopy.
Carcinogenesis 1981
PMID:Presence of benzo[a]pyrene metabolizing activities in isolated rat liver nucleoli. 627 39

Trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) and the anti-isomer of trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) were found to be activated by microsomes isolated from 3-methylcholanthrene (MC)-treated rats to reactive intermediates that bound covalently to microsomal proteins. The extent of binding was markedly reduced by the presence of reduced glutathione (GSH) or cysteine. Fluorescence spectroscopic studies on the products derived from BP-7,8-diol and BPDE after microsomal activation in presence of GSH or cysteine revealed the formation of a common reactive intermediate with unique fluorescence properties. The involvement of cytochrome P-448 in the activation of BP-7,8-diol and BPDE to protein-binding products was inferred by the requirement for NADPH and almost complete inhibition by alpha-naphthoflavone. Furthermore, microsomes from MC-treated rats could be replaced by a reconstituted system containing purified cytochrome P-448, NADPH-cytochrome reductase and co-factors. The conjugation of the reactive intermediates from BP-7,8-diol and BPDE with GSH or cysteine did not require the presence of either microsomes or cytosol, thus indicating a non-catalytic reaction. These results emphasize the importance of cellular nucleophiles such as GSH and cysteine in the deactivation of reactive benzo[a]pyrene (BP) intermediates and also provides evidence for the further activation of the ultimate carcinogen BPDE to more reactive electrophiles and may thus have relevance concerning the regulation of BP-induced carcinogenesis.
Carcinogenesis 1984 Feb
PMID:Metabolic activation of benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide to protein-binding products and the inhibitory effect of glutathione and cysteine. 642 2

Liver preparations from Syrian golden hamsters catalyze the metabolism of the pancreatic carcinogen N-nitroso-2,6-dimethylmorpholine largely to N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP). This reaction is catalyzed by a mixed-function oxidase in the presence of reduced nicotinamide adenine dinucleotide phosphate and oxygen at a rate of 3.8 nmol/min/mg of protein, and it is inhibited by known cytochrome P-450-specific inhibitors. A second potent pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) is converted to HPOP by hamster liver in which two enzyme systems appear to be involved. The first is a reductase associated with microsomes which reduces BOP to HPOP in the presence of reduced nicotinamide adenine dinucleotide at a rate of 9.1 nmol/min/mg of protein. The second enzyme is a cytosolic one which catalyzes the same reaction at a slower rate (2.3 nmol/min/mg of protein) and is more effective with reduced nicotinamide adenine dinucleotide phosphate as cofactor. Based on the amount of protein in hepatic cytosol and endoplasmic reticulum, the two enzymes may be involved to a similar extent in the reduction of BOP to HPOP in the liver. Pancreas, on the other hand, lacks the microsomal reductase for BOP but contains a cytosolic enzyme which catalyzes its reduction in the presence of reduced nicotinamide adenine dinucleotide phosphate at a rate of 0.35 nmol/min/mg of protein. Since both pancreatic carcinogens N-nitroso-2,6-dimethylmorpholine and BOP are metabolized to HPOP in the liver at rates much higher than those observed in the target organ pancreas, it is suggested that the liver may play an important role in pancreatic carcinogenesis in the hamster by these compounds.
 ...
PMID:Metabolism of pancreatic carcinogens N-nitroso-2,6-dimethylmorpholine and N-nitrosobis(2-oxopropyl)amine by microsomes and cytosol of hamster pancreas and liver. 664 May 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>