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)

Butylated hydroxyanisole (BHA), a widely used food additive, previously was found to inhibit various chemical carcinogens. In the present work, BHA, when added to the diet, inhibited the carcinogenic action of methylazoxymethanol (MAM) acetate on the large intestine of female CF1 mice. The effects of BHA on nicotinamide adenine dinucleotide (NAD+)-dependent alcohol dehydrogenase, a postulated activating enzyme for MAM, were determined. BHA reduced this enzyme activity in vitro in crude tissue preparations of large intestine and liver. The parallel finding of BHA inhibition of MAM acetate carcinogenesis of the large bowel and of NAD'-dependent dehydrogenase activity lends support to the postulated role of the dehydrogenase activity in activating MAM to an ultimate carcinogenic form. However, BHA has multiple biologic actions so that its inhibitory effect on MAM acetate-induced neoplasia of the large intestine may entail some other mechanism.
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PMID:Inhibitory effects of butylated hydroxyanisole on methylazoxymethanol acetate-induced neoplasia of the large intestine and on nicotinamide adenine dinucleotide-dependent alcohol dehydrogenase activity in mice. 22 17

Incubation of rat liver cytosolic or microsomal fractions with chromium(VI) led to a dramatic decrease in chromium(VI) mutagenicity, as determined by the Ames Salmonella assay using the TA100 tester strain. The cytosol-dependent decrease in chromium(VI) mutagenicity was found to be counteracted in the presence of dicumarol, an inhibitor of the cytosolic enzyme NAD(P)H:quinone oxidoreductase (DT-diaphorase). In order to determine whether DT-diaphorase is a significant factor in enzymatic reduction of chromium(VI) in rat liver tissue, cytosolic and microsomal fractions were analyzed for NAD(P)H-dependent chromium (VI) reductase activity leading to chromium(V) formation by using electron paramagnetic resonance (EPR) spectroscopy. Reaction of chromium(VI) with NADH or NADPH in the presence of either cytosolic or microsomal fractions led to the formation of stable chromium(V)--NAD(P)H complexes. When glucose 6-phosphate (G6P) was present in the reaction as part of a NADPH-generating system, stable chromium(V)--G6P complexes were formed in addition to the chromium(V)--NAD(P)H complexes. The chromium(V) complexes had g values of 1.980-1.982 and superhyperfine splitting constants of 0.8-0.9 characteristic of bis(diol)oxochromium(V) complexes. Inhibition of 90% of the cytosolic DT-diaphorase activity by dicumarol led to only partial (20-22%) inhibition of chromium(V) formation. Visible and EPR spectroscopic studies showed that purified DT-diaphorase had no detectable chromium(VI) reductase activity and did not catalyze formation of chromium(V). Inhibition of 69% of microsomal aryl hydrocarbon hydroxylase activity by ketoconazole led to partial (10%) inhibition of chromium(V) formation. These results indicate that intracellular NAD(P)H-dependent enzymatic reduction of chromium(VI) in rat liver cannot be attributed to the activity of any one enzyme in the cytosolic or microsomal fractions. DT-diaphorase appears to play an indirect role in decreasing chromium(VI)-induced mutagenicity in Salmonella, possibly through interaction with other redox active cellular components. The involvement of diols such as sugars and pyridine nucleotides in stabilizing intracellularly generated chromium(V) is discussed.
Carcinogenesis 1992 Jul
PMID:Reduction of chromium(VI) to chromium(V) by rat liver cytosolic and microsomal fractions: is DT-diaphorase involved? 137 26

Dihydrodiol dehydrogenase (DD; EC 1.3.1.20) purified to homogeneity from rat liver cytosol will catalyze the NAD(P)(+)-dependent oxidation of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-diol) to yield benzo[a]pyrene-7,8-dione (BPQ). To verify that BPQ is a metabolite of B[a]P-diol in rat liver, an S100 fraction was supplemented with NAD+ and NADP+, and the formation of BPQ was followed by reverse-phase HPLC. The identity of BPQ was established by co-chromatography with an authentic standard (under different solvent conditions) and by RP-HPLC using a diode-array detector which established that the metabolite shared spectral identity with BPQ. The formation of BPQ in the S100 fraction was blocked by either a competitive inhibitor (indomethacin) or a suicide substrate [1-(4-nitrophenyl)-propen-1-ol] for DD, indicating that BPQ was being formed by this enzyme. To assess the contribution of DD to the metabolism of [3H]B[a]P-diol, subcellular fractions obtained from uninduced rat liver were fortified with co-factors to optimize the activity of enzymes that would compete for this proximate carcinogen. Under these conditions, S100 fractions fortified with NAD+ and NADP+ metabolized 25% of the B[a]P-diol, producing 731 +/- 154 pmol of BPQ. In contrast, rat liver microsomes fortified with an NADPH generating system metabolize 75% of the B[a]P-diol producing 2614 +/- 379 pmoles of benzo[a]pyrene-tetrahydrotetrols. Rat liver homogenates (S10) fortified with either uridine diphosphoglucuronic acid or phosphoadenosine phosphosulfate produced 180 +/- 56 and 95 +/- 31 pmoles of conjugates respectively, which were recovered as B[a]P-diol after treatment of the aqueous phase with either beta-glucuronidase or aryl sulfatase. Of the metabolites analyzed BPQ was formed in the second largest amount. These studies show that in uninduced rat liver DD may play a significant role in the metabolism of B[a]P-diol. The metabolic fate of BPQ remains to be determined.
Carcinogenesis 1992 Sep
PMID:Contribution of dihydrodiol dehydrogenase to the metabolism of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene in fortified rat liver subcellular fractions. 139 42

The induction of quinone reductase [QR; NAD(P)H:(quinone acceptor) oxidoreductase; EC 1.6.99.2] in cultured cells and animal tissues of rodents has provided useful information on mechanisms of protection against carcinogens. We have developed a simple and efficient microtiter plate assay for the direct measurement of QR basal activity and inducibility in human peripheral blood lymphocytes (unstimulated, mitogen-stimulated and Epstein-Barr virus-transformed) grown in suspension culture. In these cells, QR was induced by monofunctional (electrophilic) inducers (i.e. 1,2-dithiole-3-thione, dimethyl fumarate, methyl vinyl sulfone) but not by bifunctional inducers (i.e. 1,1'-azonaphthalene, beta-naphthoflavone, 2,3,7,8-tetrachlorodibenzo-p-dioxin). QR is a major enzyme of xenobiotic metabolism that carries out obligatory two-electron reductions and thereby protects cells against the toxicity of quinones. It is induced in many tissues coordinately with other enzymes that protect against electrophiles. Since lymphocytes can be sampled easily and repetitively in man, this system may provide a simple short-term marker for assessing the capacity of tissues to detoxify electrophiles, such as quinones, and for measuring the response to inducers.
Carcinogenesis 1991 Dec
PMID:Induction of NAD(P)H:quinone reductase in human peripheral blood lymphocytes. 166 Jul 93

Poly(ADP-ribose) is a naturally occurring nuclear macromolecule resembling nucleic acids. It is synthesized from NAD+ on histones and a few other nuclear proteins. Its function, although not completely understood, might be to alter chromatin structure and to regulate the activity of proteins involved in the metabolism of DNA strand breaks such as ligase II, and topoisomerase I. In addition, poly(ADP-ribose) modifies proteins involved in gene expression such as acetylated histones. HMG proteins, and T antigen. The enzyme poly(ADP-ribose) polymerase responsible for this modification has the unique property of requiring nicks or free ends on the DNA for its activity and of being automodified. The automodified enzyme, presumably found at the vicinity of DNA strand breaks at damaged chromatin sites, could remove histones from DNA and attract enzymes that have an affinity for poly(ADP-ribose) such as ligase II or poly(ADP-ribose) glycohydrolase, the polymer-degrading enzyme. Alterations in chromatin structure alter gene expression and seem to be involved in repair, replication, and recombination and in changing DNA superhelical density, intermediate steps in molecular carcinogenesis. Experiments with cells in culture and laboratory animals show that inhibition of poly(ADP-ribosylation) alters transformation and tumorigenicity brought about by a great number of carcinogenic agents. Cancer can be caused by the accumulation of unrepaired DNA strand breaks in the cell accelerating gene rearrangements, deletions, insertions and amplifications. Repair of DNA strand breaks shows an absolute dependence upon the rapid synthesis and degradation of poly(ADP-ribose). The polymer has a very short half life indeed. Data are reviewed on changes in chromatin structure and function caused by histone and nonhistone poly(ADP-ribosylation). The link of this modification to transformation, tumorigenesis, development, replication and gene expression is examined. A model is proposed to explain the effect of poly(ADP-ribosylation) on chromatin structure at the molecular level. Mono- and oligo(ADP-ribosylated) histones present in nuclei under physiological conditions are proposed to functions, like acetylated histones, in maintaining chromatin loops into transcriptionally active structures. On the other hand, poly(ADP-ribosylated) histones and poly(ADP-ribosylated) enzymes such as DNA and RNA polymerases, suggested to be modified from in vitro studies, might only appear in cells that have been heavily damaged by carcinogen. Their function might be to remove histones from DNA in order to facilitate repair and to shut down transcription and replication.
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PMID:Relation between carcinogenesis, chromatin structure and poly(ADP-ribosylation) (review). 190

The effect of di(2-ethylhexyl)phthalate (DEHP) on diethylnitrosamine (DEN)-initiated preneoplastic liver lesions with expression of gamma-glutamyltranspeptidase (GGTase) and loss of adenosine triphosphatase (ATPase) as well as alterations of hepatic carbohydrate metabolism in male and female Sprague-Dawley rats have been investigated. Two treatment schedules have been compared with respect to their sensitivity by the histochemical demonstration of preneoplastic islands and by the biochemical determination of alterations in enzyme activities of liver homogenates and of serum, the last indicating hepatotoxicity. For initiation, a single dose of DEN was given, followed by treatment with various doses of DEHP given three times weekly by gavage for 7 or 11 consecutive weeks. As histochemical enzyme markers, the expression of positive GGTase as well as the deficiency in ATPase were used for identification of liver foci. The weanling female rats (protocol A) were found to be more sensitive to the carcinogenic effect of DEN in view of foci incidence than the mature male rats which underwent partial hepatectomy prior to DEN application. The administration of 200 mg DEHP/kg body wt increased the incidence of ATPase-deficient foci in both male and female rats; however, concentrations of 1000 and 2000 mg DEHP/kg decreased the incidence of liver foci. The number of foci with expression of GGTase was only slightly increased in female rats following a DEHP concentration of 50 mg/kg, and 200 mg/kg body wt. DEHP alone did not induce preneoplastic lesions that could be identified by these two markers. Biochemical investigations indicate that DEHP alters the metabolic pattern in liver. An increase of the NADP-linked enzymes glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme, extra-mitochondrial ICDH as well as an enhancement of NAD-dependent alpha-G3PDH and lactate dehydrogenase were found following DEHP administration. On the other hand the glycolytic enzymes pyruvate kinase (PK) and enolase as well as the gluconeogenetic enzyme fructose-1,6-bisphosphatase (FBPase) were significantly reduced. In protocol B (male rats) the reactions of PK, FBPase and malic enzyme were more altered after DEHP exposure than in protocol A, while the activity of G6PDH was more increased in protocol A. Most enzymes being involved in the carbohydrate metabolism are influenced by DEHP in a dose-dependent manner. There was no increase in serum FBPase activity in both male and female rats after DEHP treatment but a reduction of glutamate-oxalate-transaminase and glutamate-pyruvate-transaminase activities was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1990 Dec
PMID:Di(2-ethylhexyl)phthalate alters carbohydrate enzyme activities and foci incidence in rat liver. 197 36

The time courses of induction of liver cytosolic aldehyde dehydrogenases using benzaldehyde and propionaldehyde as substrates and NADP and NAD as co-factors after i.p. and intragastric (i.g.) administration of 2-acetylaminofluorene (2-AAF), 20-methylcholanthrene (20-MC), beta-naphthoflavone (beta-NF) and benzo[alpha]pyrene (B[alpha]P) were investigated in male Wistar rats. 2-AAF did not induce the aldehyde dehydrogenase activities with any substrate:co-factor combination. The other three inducers all induced the oxidation of the aldehydes in a reversible manner. With an i.p. route of administration (one daily dose for four consecutive days) (20-MC) was the most potent inducer giving a 240-fold increase of benzaldehyde: NADP activity on the ninth day. beta-NF elevated the activity 20-fold with peak activity at day 7, while B[alpha]P gave maximal induction on day 5 with a 60-fold increase in activity over the corresponding value for normal liver. The i.g. administration resulted in a weaker but coordinated induction of activity with peak activity on the sixth day for the different inducers. The activity ratio benzaldehyde:NADP/propionaldehyde:NAD, 0.78 in normal rats, was altered in all induced states to a level close to 4. The interpretation of our work supports the hypothesis that the inducers in this respect use the same mechanisms of induction. The differences noted can be explained by variations in the exposure of the liver to the administered dose and/or by differences in receptor affinity. The inducibility of benzaldehyde:NADP aldehyde dehydrogenase in rat liver exceeds by orders of magnitude the ability of the same inducers to increase the amount of the activity of other drug metabolizing enzymes such as glutathione S-transferase, cytochrome P450 and cytochrome b5. The reversible, drug-dependent induction characterized in normal rat liver in this work differs entirely from the persistent constitutive elevation of the same enzymes in preneoplastic liver nodules.
Carcinogenesis 1991 May
PMID:Kinetics of induction of cytosolic benzaldehyde: NADP and propionaldehyde: NAD aldehyde dehydrogenase activities in rat livers from male Wistar rats. 202 38

The catalytic activity of the nuclear enzyme poly(ADP-ribose) polymerase (NAD+ ADP-ribosyl transferase, EC 2,4,2,30) is totally dependent upon the presence of DNA strand breaks. Having isolated a full-length cDNA for the polymerase, we have now evaluated the effect of endogenously and exogenously induced DNA strand breaks on the transcriptional control of this enzyme. During retinoic acid or dimethyl-sulfoxide-induced differentiation of HL-60 human leukemia cells, which may involve DNA breaks as well as other changes in chromatin, mRNA levels for the polymerase increased very early and remained high for up to 48 h after which it decreased to pre-induced levels. Polymerase transcript levels did not change, however, during the induction of DNA strand breaks by dimethylsulfate, a variety of other alkylating agents, X-irradiation, or UV-irradiation in several mammalian cell lines. It appears that in sharp contrast to the catalytic requirement of the polymerase, the induction of transcription of the polymerase gene may not be a strand-break-dependent process. The noninducibility of the polymerase gene following DNA damage suggested that there may be adequate levels of the polymerase in the cells to cope with DNA damage. To test this hypothesis we examined the efficacy of DNA repair in Cos cells engineered to overexpress the polymerase. Although there was a slight augmentation of the repair rate, this increase was apparent only after very high levels of DNA damage and only at early repair times. After a longer repair period, the extent of repair in control cell was similar to that in the cell overexpressing the polymerase. We thus conclude that the basal levels of the polymerase are adequate for significant amounts of DNA damage.
Carcinogenesis 1990 Jan
PMID:Expression of the poly(ADP-ribose) polymerase gene following natural and induced DNA strand breakage and effect of hyperexpression on DNA repair. 210 80

The effect of dietary intake of butylated hydroxytoluene (BHT) (0.6%) on the in vivo distribution, metabolism and DNA-binding of intragastrically administered 7,12-dimethylbenz[a]anthracene (DMBA) was evaluated. Urinary excretion of DMBA increased, blood content of metabolized DMBA increased and blood content of non-metabolized DMBA decreased for rats fed the diet containing BHT as compared to rats fed the control diet. The binding of DMBA to both liver and mammary DNA decreased for rats fed the diet containing BHT as compared to controls. The liver activities of glutathione-S-transferase (GST), epoxide hydrolase (EH) and NAD(P)H-quinone reductase (QR) increased in response to BHT feeding. However, no increase in the mammary tissue activities of these enzymes was observed. These results suggest that the ability of dietary BHT to inhibit the initiation of DMBA-induced mammary carcinogenesis partly may be due to decreased binding of DMBA to mammary DNA. This effect of BHT is not due to an increase in mammary tissue activities of GST, EH and QR, enzymes involved in carcinogen detoxification, but may involve increased liver metabolism of DMBA to products that do not bind to DNA.
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PMID:Effect of dietary butylated hydroxytoluene on the in vivo distribution, metabolism and DNA-binding of 7,12-dimethylbenz[a]anthracene. 210 65

Poly ADP-ribosylation is a post-translational modification of chromatin proteins catalyzed by the enzyme poly-ADPR transferase (poly-ADPRT) and affects the structure as well as the functional properties of chromatin. It is of particular relevance in carcinogenesis, as it represents an epigenetic mechanism for modulation of gene expression. In the present study, A431 cells were exposed to tumor promoters phorbol-12-myristate-13-acetate (PMA), benzoyl peroxide (BP), mezerein and 6-keto-lithocholic acid (KA), and their effect on poly-ADP-ribosylation was studied. All these tumor promoters increased the activity of poly-ADPRT in these cells--PMA 2.3-fold, BP and mezerein 2.2-fold each and KA 1.3-fold. The enzyme inhibitor 3-amino benzamide (3AB) partially prevented the stimulation of poly-ADPRT by these promoters. There was a concomitant decrease in NAD levels, the substrate for poly-ADPRT. The decrease was 44% for PMA, 46% for BP, 21% for KA and 34% for mezerein. The induction of poly-ADP-ribose synthesis by PMA and BP appears to be mediated at least in part by active oxygen species, as they induced an increase in superoxide anions and anti-oxidants prevented the increase of poly-ADPRT activity to varying extents.
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PMID:A comparative study on the effect of tumor promoters on poly ADP-ribosylation in A431 cells. 212 Jan 35


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