Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.99.3 (diaphorase)
 5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enhanced lipid peroxidation potential was measured in Holtzman rat colon tumors induced by chronic subcutaneous injection of 1,2-dimethyl-hydrazine as compared with normal colonic tissue. The peroxidation potentials were determined in the mitochondrial cellular components by measuring the ferrous-ascorbate induced formation of malondialdehyde. The tumor mitochondria were found to peroxidize at a rate 8-10-fold higher than the comparable normal tissue components. In addition, we found that the mitochondria from the cancer cells exhibited reduced NADH-cytochrome c reductase activity. These observations suggest an involvement of non-enzymatic free radical flux in DMH-induced carcinogenesis, which may be the result of structurally altered mitochondrial membranes.
Cancer Lett 1980 May
PMID:Evidence for a defective mitochondrial membrane in 1,2-dimethylhydrazine-induced colon adenocarcinoma in rat: enhanced lipid peroxidation potential in vitro. 722 56

Aryl hydrocarbon hydroxylase (AHH) activity, NADH-dependent cytochrome c reductase (cyt c) activity, and [3H]thymidine (3H-TdR) incorporation were monitored in human lymphocytes cryopreserved for periods up to 1 year. A standard procedure for freezing, thawing and culturing of these lymphocytes was developed. Kinetics for expression of benz[a]anthracene-(BA)-induced AHH activity, cyt c activity, and 3H-TdR incorporation were similar in both freshly cultured and cryopreserved cells. Lymphocyte samples from 10 individuals were collected once per month over a 3-month period and cells were either cultured at the time of donation or cryopreserved for later assay. Results indicated that the cryopreserved lymphocytes efficiently responded to mitogen activation. The intra-individual variation in AHH activities was reduced in the cryopreserved lymphocytes compared to the freshly cultured cells, and the relative ranking of these individuals in terms of their AHH activities remained constant for both fresh and cryopreserved samples. Cryopreservation seems to offer significant advantages over the freshly cultured lymphocytes because it allows for lymphocyte samples to be collected in diverse geological locations and over extended periods of time and yet permits for the culture and assay of all the cell samples at exactly the same time.
Cancer Lett 1981 Oct
PMID:A method for detecting aryl hydrocarbon hydroxylase activities in cryopreserved human lymphocytes. 729 39

The expression of nitric oxide synthase (NOS) was studied by NAD(P)H diaphorase histochemical localization method in (i) individual cells of the normal colonic mucosa (n = 13) which served as control, (ii) colonic polyps (n = 14), (iii) colonic carcinoma (n = 20) and (iv) peritumoral mucosa (2 and 5 or 10 cm away from the tumor). Four of the tumor specimens had normal epithelium adjacent to the cancer, which thus served as an internal control. The expression of NOS activity in colon cancer was significantly reduced as compared to the control group of individuals (P < 0.004); undetectable in 25%, diminished in 45%, normal in 30%. On comparing the expression in normal mucosa and polyps there was a significant reduction of the expression in polyps (P < 0.027); undetectable in 14%, reduced in 35%, normal in 51%. When compared to the peritumoral mucosa at 2 and 10 cm the tumor showed a significant reduction in expression of NOS activity (P < 0.001 and P < 0.0001 respectively). There was no significant difference seen in the expression at 2 and 10 cm (P = 0.329). The peritumoral mucosa at a distance of 2 cm away from the tumor when compared to the control mucosa showed no significant difference (P = 1.000), although there is a tendency to a high normal expression of NOS activity in the mucosa at a distance of 2 cm. Similarly, there was no significant difference between the control mucosa and the peritumoral mucosa obtained at a distance of 10 cm (P = 0.383). The expression of NOS activity in all tissues examined was abolished by preincubation of tissue with the selective NOS inhibitor L-NMMA but not with D-NMMA. Our data showed extensive and significant reduction as identified by the NAD(P)H diaphorase method in the expression of NOS activity, thereby reflecting the activity of nitric oxide in colon cancer and colonic polyps. The generalized suppression of this activity, which precedes the onset of overt neoplasia, may be an important event in colon carcinogenesis. This aberrant expression could also be compatible with the selective advantage to either tumor promotion and metastatic progression or to tumoricidal activity.
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PMID:Aberrant expression of nitric oxide synthase in human polyps, neoplastic colonic mucosa and surrounding peritumoral normal mucosa. 752 94

Quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2], also called DT diaphorase, is a homodimeric FAD-containing enzyme that catalyzes obligatory NAD(P)H-dependent two-electron reductions of quinones and protects cells against the toxic and neoplastic effects of free radicals and reactive oxygen species arising from one-electron reductions. These two-electron reductions participate in the reductive bioactivation of cancer chemotherapeutic agents such as mitomycin C in tumor cells. Thus, surprisingly, the same enzymatic reaction that protects normal cells activates cytotoxic drugs used in cancer chemotherapy. The 2.1-A crystal structure of rat liver quinone reductase reveals that the folding of a portion of each monomer is similar to that of flavodoxin, a bacterial FMN-containing protein. Two additional portions of the polypeptide chains are involved in dimerization and in formation of the two identical catalytic sites to which both monomers contribute. The crystallographic structures of two FAD-containing enzyme complexes (one containing NADP+, the other containing duroquinone) suggest that direct hydride transfers from NAD(P)H to FAD and from FADH2 to the quinone [which occupies the site vacated by NAD(P)H] provide a simple rationale for the obligatory two-electron reductions involving a ping-pong mechanism.
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PMID:The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction. 756 29

Integrating microdensitometry has been used to quantitate changes in 4 cytoplasmic enzymes (NADH dehydrogenase, succinate dehydrogenase, acid phosphatase and alpha-naphthyl butyrate esterase), DNA, RNA and glycogen in developing macrophages from 17 patients with non-Hodgkin's lymphoma and 19 normal subjects. Cytochemical measurements were made at intervals over 6 days of suspension culture; over 16 000 individual cells were examined in total and the results subjected to analysis of variance. While the levels of enzymes and RNA of both groups showed increases over the period of culture, the levels of alpha-naphthyl butyrate esterase in the patients' cells were consistently lower than the corresponding values for the normal cells and glycogen levels were higher, these differences satisfying the pre-determined requirements for statistical significance. It is concluded that (a) maturational changes take place in cytochemical constituents of developing macrophages of non-Hodgkin's lymphoma (b) there are disturbances affecting the amounts of the specific enzyme alpha-naphthyl butyrate esterase and glycogen (c) these abnormalities may be part of a compromise of host defense mechanisms by the disease, although a pre-existing defect in esterase increasing the susceptibility to malignancy is another possibility, and (d) the methods used may be of value in future investigations of the cause of the disturbances and their correction.
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PMID:Abnormalities of esterase and glycogen in developing macrophages in non-Hodgkin's lymphoma: a quantitative cytochemical study. 757 45

Using five- to eight-week-old male F344 rats and a high-fat (23.5% corn oil) modified AIN-76A diet, we examined the effects of dietary restriction (a 3-wk 30% reduction of food intake with respect to ad libitum-fed controls) or complete fasting (2 days without food) on the activities of hepatic xenobiotic metabolizing enzymes in vitro and on azoxymethane- (AOM) induced formation of O6-methylguanine and 7-methylguanine in liver and colon DNA in vivo. Compared with ad libitum-fed rats, fasting increased total liver cytochrome P450 by 32%, microsomal aniline hydroxylase by 270%, N-nitrosodimethylamine demethylase by 270%, and azoxymethane hydroxylase by 320%. Liver benzo[a]pyrene (BP) hydroxylase and glutathione-S-transferase were decreased by 39% and 21%, respectively, whereas NADPH cytochrome c reductase and UDP glucuronyltransferase were unchanged. DNA methylation in the livers of fasted animals was 20-31% greater six hours after a 15 mg/kg sc injection of AOM than in ad libitum-fed controls, whereas DNA methylation in the colon was slightly lower. In three-week diet-restricted animals. there were small but not statistically significant changes in the various enzyme activities and in AOM-induced DNA methylation compared with the ad libitum-fed controls, with the exception of BP hydroxylase, which showed a 26% decrease. However, the trends in the increase or decrease of each parameter, although small in magnitude, were similar to those observed in the case of fasting, suggesting that the effects might become significant if the duration of diet restriction were prolonged. The enhancement of AOM metabolism in rat liver by fasting, leading to increased liver DNA methylation, is different from that produced by chemical inducers, such as ethanol, where no increase in liver DNA methylation is observed.
Nutr Cancer 1995
PMID:Effects of dietary restriction and fasting on selected rat liver enzymes of xenobiotic metabolism and on AOM-induced DNA guanine methylation in rat liver and colon. 773 11

To understand the mechanism of action of the antitumor arotinoid mofarotene (Ro 40-8757), differential screening of cDNA libraries with cDNA probes prepared from treated or untreated breast-cancer cells was performed. Several genes were identified that appeared to be regulated by mofarotene, including a mitochondrial gene encoding a subunit of NADH dehydrogenase (NDI). This gene was down-regulated in the breast-cancer cell line MDA-MB-231 after treatment with the arotinoid for 3 to 6 hr. Down-regulation of NDI was detected in 2 other breast-carcinoma cell lines (ZR-75-I and MCF-7) and a pancreatic cancer cell line (BxPC3), but not in the normal fibroblast cell line Wi-38 or several other tumor cell lines. This effect was blocked by addition of cycloheximide to the medium. The retinoids, all-trans and 9-cis retinoic acids, did not affect the expression of NDI in MDA-MB-231 cells, demonstrating that mofarotene was not acting through the nuclear retinoic-acid receptors. In the estrogen-receptor-expressing breast-cancer line ZR-75-I, tamoxifen had no effect on NDI expression. The cytotoxic drugs doxorubicin, 5-FU and vincristine also had no effect on regulation of this gene. Two mitochondrial proteins encoded in the nucleus, ATPase beta subunit and mitochondrial transcription factor I, were not down-regulated by mofarotene. Addition of mofarotene to cells incubated in glucose-free medium led to their death. These results indicate that down-regulation of mitochondrial gene transcription is specific to mofarotene and may explain, in part, the anti-proliferative effects of this compound.
Int J Cancer 1994 Sep 15
PMID:Down-regulation of mitochondrial gene expression by the anti-tumor arotinoid mofarotene (Ro 40-8757). 792 84

Anthraquinone derivatives are important anti-cancer drugs possessing undesirable cardiotoxic properties related to their peroxidating activity. Previous studies have suggested that this activity can be caused by the binding of a singlet oxygen molecule to an anthraquinone, followed by the one-electron reduction of the complex formed, and its further dissociation into anthraquinone and the superoxide anion radical. In this study, we have carried out semi-empirical PM3 calculations of the energetics of the formation of peroxides and hydroperoxides from hydroxy, amino and imino derivatives of 9,10-anthracenedione. These calculations were supplemented with ab initio calculations, using STO-3G, 4-31G and 6-31G basis sets, on the energetics of oxygen binding to 1,4-dihydroxy and 1,4-diaminobenzene. It was found that for anthraquinones possessing hydroxyl groups, the formation of hydroperoxides is significantly favored energetically compared with the formation of peroxides. In the case of anthraquinones containing only amino groups, the formation of hydroperoxides is less favorable, owing to a greater enthalpy of amino group deprotonation compared with that of hydroxyl group. The effect of electrostatic solvation on the energetics of oxygen addition was also investigated using the Conductor-like Screening Model (COSMO) approach. The effect of solvation on peroxide formation was found to be small, while in the case of hydroperoxides solvation was found to lower the enthalpy of this reaction by approximately 10 kcal/mol for epsilon = 78 (simulating an aqueous environment). Significant stabilization of hydroperoxides was estimated in weakly polar media (epsilon = 4) which can simulate the quinone-reducing center of the mitochondrial NADH dehydrogenase. The enthalpies obtained for oxygen addition to anthraquinones involving the formation of the most stable of the peroxide and hydroperoxide species are in good correlation with the rates of NADPH oxidation stimulated by these compounds and, in turn, with their peroxidating properties. This correlation can be directly implemented in the design of non-peroxidating anthraquinone-derived anti-cancer drugs.
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PMID:Enthalpy of oxygen addition to anthraquinone derivatives determines their ability to mediate NADH oxidation. 794 27

The chemopreventive role of an Indian medicinal plant Mikania cordata (Compositae), which is consumed as vegetable and advocated in folk-medicine, has been evaluated through its effects on Phase 1 and 2 of the hepatic drug-detoxifying enzyme system in rats. Although oral administration of a methanolic extract of this plant root (50, 100 or 150 mg/kg for 4, 8 or 12 weeks) has been found to have very little or no effect on hepatic microsomal cytochrome P-450 and cytochrome b5 contents as well as NADPH cytochrome c reductase activity, it afforded a marked induction of uridine diphosphoglucuronyl transferase activities of liver microsomes. The extract also significantly increased the activities of microsomal uridine diphosphoglucose dehydrogenase, reduced nicotinamide adenine dinucleotide (phosphate): quinine reductase and cytosolic glutathione s-transferases with a concomittant elevation in the contents of reduced glutathione. All these effects were found to be dose-dependent and maintained during 12 weeks of the extract treatment. Results of the study clearly indicate that the intracellular contents of active intermediates of various xenobiotics including chemical carcinogens would be reduced by the specific enhancement of drug-detoxifying enzymes in the liver of rats treated with the plant extract.
Cancer Lett 1994 Jun 30
PMID:Anticarcinogenic biological response of Mikania cordata: reflections in hepatic biotransformation systems. 801 37

The effects of a series of D- and L-amino acid alcohols on the proliferation and phenotypic expression of B16 mouse melanoma cells were evaluated. B16 melanoma cells were incubated for different time intervals in the presence of D- or L-phenylalaninol (PHE), D- or L-alaninol (AL), D- or L-leucinol (LE), L-histidinol (HIS), L-tyrosinol (TYR) and L-methioninol (MET). All agents, including the D or L configuration, induced an anti-proliferative effect, although of considerably different magnitude. D-PHE was the most active growth inhibitor. The growth inhibitory effects were accompanied by phenotypic alterations, which included morphological changes and enhancement in the activities of NADPH cytochrome c reductase and tau-glutamyl transpeptidase. These phenotypic alterations correlated with the growth inhibitory effects of the different agents and seem to reflect a higher differentiated state.
Cancer Lett 1993 May 14
PMID:Amino acid alcohols: growth inhibition and induction of differentiated features in melanoma cells. 809 46


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