Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of naturally occurring as well as synthetic structural analogs of the dietary constituent curcumin were examined in order to elucidate which portions of the molecule are critical for the ability to induce Phase 2 detoxification enzymes in murine hepatoma cells, and hence to assess the chemoprotective potential of these compounds. Two groups of compounds were studied: classical Michael reaction acceptors such as curcumin and related beta-diketones such as dibenzoylmethane which lack direct Michael reactivity. The presence of two structural elements was found to be required for high inducer potency: (i) hydroxyl groups at ortho-position on the aromatic rings and (ii) the beta-diketone functionality. All curcuminoids elevate the specific activity of quinone reductase in both wild type and mutant cells defective in either the aryl hydrocarbon (Ah) receptor or cytochrome P4501A1 activity. This indicates that neither binding to this receptor, nor metabolic activation by P4501A1 are required for the signaling process originating from this family of electrophiles and ultimately resulting in Phase 2 enzyme induction.
Carcinogenesis 1999 May
PMID:Relation of structure of curcumin analogs to their potencies as inducers of Phase 2 detoxification enzymes. 1033 11

Carcinogen-DNA adducts may represent an intermediate end-point in the carcinogenic cascade and may reflect exposure to chemical carcinogens, as well as susceptibility and, ultimately, cancer risk. Interindividual variability in activity of enzymes involved in the metabolism of polycyclic aromatic hydrocarbons to mutagenic diol epoxides may predict adduct levels and, indirectly, lung cancer risk. Using 32P-postlabeling methods, the levels of bulky DNA adducts were determined in macroscopically normal bronchial tissues obtained from resected lobes of 143 Hungarian patients with lung malignancy and other pulmonary conditions. DNA from normal tissue was also evaluated for polymorphisms in cytochrome P450 2C9 (CYP2C9) at two sites, codons 144 (Arg/Cys) and 359 (Ile/Leu), for glutathione S-transferase P1 (GSTP1) at codon 105 and for NAD(P)H:quinone oxidoreductase (NQO1) at codon 187 (Pro/Ser). Using the Mann-Whitney U-test and analysis of variance, levels of adducts were evaluated in relation to variant genotypes, separately for smokers and non-smokers. As previously reported, bulky DNA adduct levels in smokers (n = 104) were estimated to be 54% higher than in non-smokers (n = 39) (8.6 +/- 4.2 versus 5.6 +/- 3.3 per 10(8) nucleotides, respectively, P < 0.01). Adduct levels were 16-29% higher in individuals with the homozygous Ile359/Ile359 CYP2C9 allele than in those heterozygous for the variant allele (Ile359/Leu359) [8.8 +/- 4.3 (n = 84) versus 7.6 +/- 3.5 (n = 20) for smokers and 5.8 +/- 3.5 (n = 32) versus 4.5 +/- 1.3 (n = 7) for non-smokers], although differences were not statistically significant. There were no clear differences in adduct levels in relation to genotypes of NQO1 or GSTP1. Although numbers of patients in this study are large in relation to many studies of carcinogen-DNA adducts, it is still possible that significant differences were not noted for polymorphisms in xenobiotic metabolizing enzymes due to relatively small numbers in stratified data.
Carcinogenesis 1999 Jun
PMID:Analyses of bronchial bulky DNA adduct levels and CYP2C9, GSTP1 and NQO1 genotypes in a Hungarian study population with pulmonary diseases. 1035 78

Glutathione S-transferase GSTM1 B and GSTT1 null, and cytochrome P450 CYP2D6 EM have been associated with cutaneous basal cell carcinoma (BCC) numbers, although their quantitative effects show that predisposition to many BCC is determined by an unknown number of further loci. We speculate that other loci that determine response to oxidative stress, such as NAD(H):quinone oxidoreductase (NQO1) are candidates. Accordingly, we assessed the association between NQO1 null and BCC numbers primarily to rank NQO1 null in a model that included genotypes already associated with BCC numbers. We found that only 14 out of 457 cases (3.1%) were NQO1 null. This frequency did not increase in cases with characteristics linked with BCC numbers including gender, skin type, a truncal lesion or more than one new BCC at any presentation (MPP). However, the mean number of BCC in NQO1*0 homozygotes was greater than in wild-type allele homozygotes and heterozygotes, although the difference was not quite significant (P = 0.06). These data reflect the link between NQO1 null and BCC numbers in the 42 MPP cases rather than the whole case group. We identified an interaction between NQO1 null and GSTT1 null that was associated with more BCC (P = 0.04), although only four cases had this combination. The relative influence of NQO1 null was studied in a multivariate model that included: (i) 241 patients in whom GSTM1 B, GSTT1 null and CYP2D6 EM genotype data were available, and (ii) 101 patients in whom these genotypes, as well as data on GSTM3, CYP1A1 and melanocyte-stimulating hormone receptor (MC1R) genotypes were available. NQO1 null (P = 0.001) and MC1R asp294/asp294 (P = 0.03) were linked with BCC numbers, and the association with CYP2D6 EM approached significance (P = 0.08). In a stepwise regression model only these genotypes were significantly associated with BCC numbers with NQO1 null being the most powerful predictor.
Carcinogenesis 1999 Jul
PMID:Association of NAD(P)H:quinone oxidoreductase (NQO1) null with numbers of basal cell carcinomas: use of a multivariate model to rank the relative importance of this polymorphism and those at other relevant loci. 1038 95

The modifying effect of dietary exposure to a flavonoid morin during the initiation and post-initiation phases of azoxymethane (AOM)-initiated colorectal carcinogenesis was investigated in male F344 rats. A total of 55 animals were initiated with AOM by weekly s. c. injections of 15 mg/kg body wt for 3 weeks to induce colorectal neoplasms. Rats were fed a diet containing 500 p.p.m. morin for 5 ('initiation feeding') or 28 ('post-initiation feeding') weeks. Other groups contained rats treated with morin alone (500 p.p.m. in diet) and untreated rats. At the end of the study (32 weeks), the incidence of adenocarcinoma in the large intestine of rats initiated with AOM together with (43%) or followed by (29%) a diet containing morin was smaller than that of rats given AOM alone (75%). A significant difference was found between 'post-initiation feeding' and untreated groups (P = 0.023). Although both 'initiation feeding' and 'post-initiation feeding' of morin reduced polyamine levels in colorectal mucosa and blood, 'post-initiation feeding' of morin significantly decreased the proliferating cell nuclear antigen-positive index in aberrant crypt foci. 'Post-initiation feeding' of morin significantly elevated glutathione S-transferase and quinone reductase activities in the liver and large bowel, but 'initiation feeding' caused a significant elevation of these enzymes activities only in the large bowel. These results indicate that morin could exert a weak chemopreventive effect on large bowel tumorigenesis induced by AOM when fed during the post-initiation phase.
Carcinogenesis 1999 Aug
PMID:Modifying effects of a flavonoid morin on azoxymethane-induced large bowel tumorigenesis in rats. 1042 95

Our recent studies have shown that vanadium, a dietary micronutrient, has an inhibitory response against experimentally induced rat liver carcinogenesis. In the present study, the effect of vanadium on hepatic xenobiotic biotransformation in rats exposed to diethylnitrosamine (DENA, 200 mg/kg, IP) was investigated to elucidate a possible mechanism of vanadium-mediated prevention of chemical carcinogenesis. Supplementary vanadium in drinking water at 0.5 parts per million (ppm) was employed ad lib before and after the intiation with DENA, before the initiation only, or during the promotional event. After 20 weeks, there was a significant reduction of hepatocyte nodules (HNs) (P<0.01), nodule multiplicity (P<0.001), and the number of nodules more than 3 mm in size in the long-term vanadium-supplemented rats than their DENA control counterparts. Total cytochrome P450 and b5 contents as well as cytochrome P450 2E1 (CYP2E1, EC 1.5.99), aryl hydrocarbon hydroxylase (AHH, EC 1.14.14.2), and UDP-glucuronyl transferase (UDPGT, EC 2.4.1.17) activities in the microsomal fractions of HNs and nonnodular surrounding parenchyma (NNSP) were found to be significantly decreased in DENA control group compared to untreated normal control. Though supplementary vanadium had little or no influence on the contents of cytochrome P450 and b5 and activities of CYP2E1 and AHH in HNs and NNSP, it substantially elevated the UDPGT activity in both HNs and NNSP liver areas. DENA treatment alone also brought about a sharp decrease in cytosolic UDP-glucose dehydrogenase (EC 1.1.1.22), DT-diaphorase (EC 1.6.99.2), and glutathione S-transferase (EC 2.5.1.18) activities in HNs and NNSP compared to normal liver. Supplementary vanadium was found to exert a marked induction in these cytosolic enzymes in HNs as well as NNSP when compared to DENA control. A positive correlation of phase I and phase II drug metabolizing enzymes in HNs or NNSP was always observed in DENA or DENA plus long-term vanadium-treated group. It is concluded that the chemoprotective effect of vanadium may be attributed to the substantial elevation of phase II conjugating enzymes, which may lead to a move and shift of the metabolic profile that may reduce the intracellular concentration of carcinogen-derived reactive intermediates.
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PMID:Characterization of selective induction and alteration of xenobiotic biotransforming enzymes by vanadium during diethylnitrosamine-induced chemical rat liver carcinogenesis. 1045 Oct 30

The modifying effects of dietary exposure of the flavonoid morin on 4-nitroquinoline 1-oxide (4-NQO)-induced tongue tumorigenesis, the activities of phase II detoxifying enzymes glutathione S-transferase (GST) and quinone reductase (QR) in liver and tongue, and cell proliferation activity in tongue were investigated in male F344 rats. At 7 weeks of age, all animals except those treated with morin alone and control group were given 4-NQO (20 ppm) in drinking water for 8 weeks to induce oral neoplasms. Starting 7 days before 4-NQO exposure, experimental groups were fed experimental diets containing morin (100 and 500 ppm) for 10 weeks ("initiation feeding"). Starting 1 week after the cessation of exposure to 4-NQO, other experimental groups given 4-NQO and a basal diet were given experimental diets for 22 weeks ("post-initiation feeding"). At week 32 week, "initiation feeding" of morin caused a significant reduction in the incidence of tongue carcinoma (by 44-100%). "Post-initiation feeding" with morin also significantly decreased the frequency of tongue carcinoma (by 44%). Morin feeding elevated liver GST and QR activities and GST activity in the anterior portion of tongue. Feeding with morin significantly lowered QR activity of the posterior part of the tongue. Dietary exposure to morin significantly decreased the proliferating cell nuclear antigen-positive index in the posterior portion. Also, morin feeding lowered tongue polyamine levels, especially in the "post-initiation feeding" group. Our results indicate that morin acts as a chemopreventive agent against tongue carcinogenesis induced by 4-NQO through modification of detoxifying enzyme activities and/or cell proliferation activities.
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PMID:Chemopreventive effect of dietary flavonoid morin on chemically induced rat tongue carcinogenesis. 1049 31

Isoflavones in soy may play a role in the prevention of cancer through their capacity to affect antioxidant or protective phase II enzyme activities. This study evaluated the effects of dietary isoflavone levels on the induction of antioxidant and phase II enzyme activities and inhibition of breast carcinogenesis. Female Sprague-Dawley rats (36 d) were fed one of four purified diets with casein, or with soy containing three levels of isoflavonoids (0.03, 0.4 or 0.81 mg/g diet; low, middle and high level of isoflavones, respectively). After 2 wk, enzyme activity was determined of rats (n = 6-7) from each diet group. Liver glutathione peroxidase and glutathione reductase activities, blood glutathione levels, kidney glutathione S-transferase and colon quinone reductase (QR) activities were greater in rats consuming the high isoflavone diet compared to rats consuming the casein diet. Kidney QR and liver, kidney, small intestine, and colon UDP-glucuronosyltransferase activities were greater in rats fed the high isoflavone diet compared to rats fed the casein and low-isoflavone diets. Liver and blood oxidized glutathione were lower in rats fed the high-isoflavone diet compared to those fed the low-isoflavone diet. A subset of rats (n = 86) was fed the purified diets for 2 wk and intubated with dimethylbenz[a]anthracene or peanut oil and palpated weekly for tumors. At 13 wk, there was an inverse relationship (R(2) = 0.911, P < 0.09) between tumor incidence and increasing isoflavone intake. These data support the mechanism of soy and soy isoflavones as antioxidant and phase II enzyme inducers, but not as tumor inhibitors.
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PMID:Soy induces phase II enzymes but does not inhibit dimethylbenz[a]anthracene-induced carcinogenesis in female rats. 1049 53

Polyphenolic antioxidants are being identified as cancer preventive agents. Recent studies in our laboratory have identified and defined the cancer preventive and anticarcinogenic potential of a polyphenolic flavonoid antioxidant, silymarin (isolated from milk thistle). More recent studies by us found that these effects of silymarin are due to the major active constituent, silibinin, present therein. Here, studies are done in mice to determine the distribution and conjugate formation of systemically administered silibinin in liver, lung, stomach, skin, prostate and pancreas. Additional studies were then performed to assess the effect of orally administered silibinin on phase II enzyme activity in liver, lung, stomach, skin and small bowel. For tissue distribution studies, SENCAR mice were starved for 24 h, orally fed with silibinin (50 mg/kg dose) and killed after 0.5, 1, 2, 3, 4 and 8 h. The desired tissues were collected, homogenized and parts of the homogenates were extracted with butanol:methanol followed by HPLC analysis. The column eluates were detected by UV followed by electrochemical detection. The remaining homogenates were digested with sulfatase and beta-glucuronidase followed by analysis and quantification. Peak levels of free silibinin were observed at 0.5 h after administration in liver, lung, stomach and pancreas, accounting for 8.8 +/- 1.6, 4. 3 +/- 0.8, 123 +/- 21 and 5.8 +/- 1.1 (mean +/- SD) microg silibinin/g tissue, respectively. In the case of skin and prostate, the peak levels of silibinin were 1.4 +/- 0.5 and 2.5 +/- 0.4, respectively, and were achieved 1 h after administration. With regard to sulfate and beta-glucuronidate conjugates of silibinin, other than lung and stomach showing peak levels at 0.5 h, all other tissues showed peak levels at 1 h after silibinin administration. The levels of both free and conjugated silibinin declined after 0.5 or 1 h in an exponential fashion with an elimination half-life (t((1/2))) of 57-127 min for free and 45-94 min for conjugated silibinin in different tissues. In the studies examining the effect of silibinin on phase II enzymes, oral feeding of silibinin at doses of 100 and 200 mg/kg/day showed a moderate to highly significant (P < 0.1-0.001, Student's t-test) increase in both glutathione S-transferase and quinone reductase activities in liver, lung, stomach, skin and small bowel in a dose- and time-dependent manner. Taken together, the results of the present study clearly demonstrate the bioavailability of and phase II enzyme induction by systemically administered silibinin in different tissues, including skin, where silymarin has been shown to be a strong cancer chemopreventive agent, and suggest further studies to assess the cancer preventive and anticarcinogenic effects of silibinin in different cancer models.
Carcinogenesis 1999 Nov
PMID:Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. 1054 12

Black tea extracts (hot aqueous, polyphenols and theaflavins) and green tea extracts (hot aqueous, polyphenols, epicatechin, epicatechin gallate, epigallocatechin and epigallocatechin gallate) were tested in nine standardized cell culture assays for comparative cancer chemopreventive properties. Most black and green tea extracts strongly inhibited neoplastic transformation in mouse mammary organ cultures, rat tracheal epithelial cells and human lung tumor epithelial cells. Nearly all tea fractions strongly inhibited benzo[a]pyrene adduct formation with human DNA. Induction of phase II enzymes, glutathione-S-transferase and quinone reductase, were enhanced by nearly all tea fractions, while glutathione was induced by only a few fractions. Ornithine decarboxylase activity was inhibited by nearly all the green tea fractions, but none of the black tea fractions. 12-O-tetradecanoylphorbol-13-acetate-induced free radicals were inhibited by most tea fractions. These results provide strong evidence of both anti-mutagenic, anti-proliferative and anti-neoplastic activities for both black and green tea extracts. Such anticancer mechanisms may well be responsible for the cancer preventive efficacies seen in both experimental and human studies.
Carcinogenesis 2000 Jan
PMID:Comparative chemopreventive mechanisms of green tea, black tea and selected polyphenol extracts measured by in vitro bioassays. 1060 35

The 'Mediterranean diet', a diet rich in cereals, fruit and vegetables, has been associated with lowering the risk of a variety of cancers of the digestive tract and the bladder. In a previous study, we showed that the high phenolic content these dietary components produce in the urine could be associated with higher antimutagenic properties of the urine and lower arylamine-DNA adducts in exfoliated bladder cells. We have conducted a case-control study on 162 bladder cancer patients and 104 hospital controls. Total aromatic DNA adducts were measured in white blood cells (WBC) of all subjects by (32)P-post-labelling. Genetically based metabolic polymorphisms were analysed by PCR-RFLP (NAT2, GSTM1, GSTT1, GSTP1, COMT and NQO1). All subjects were interviewed about their tobacco use, dietary habits and other risk factors. The odds ratio (OR) for the risk of bladder cancer according to the presence/absence of WBC DNA adducts (detection limit 0.1 RALx10(8)) was 3.7 [95% confidence interval (CI) 2.2-6.3] and a dose-response relationship with levels of adducts was apparent. The association between case/control status and the presence of WBC DNA adducts was significantly stronger in the subjects who consumed fewer portions of fruit or vegetables per day (OR 7.80, 95% CI 3.0-20.30 for 0-1 portions of vegetables) than in the heavy consumers (OR 4.98 for consumers of 2 portions daily, OR 1.97 for consumers of > or =3 portions; similar but lower estimates were found for the intake of fruit). No association was noticed between tobacco smoking and WBC DNA adducts. Only NAT-2, among the several genotypes considered, was associated in a statistically significant way with the risk of bladder cancer (OR 1.72, 95% CI 1.03-2.87) and with the levels of WBC DNA adducts. Our report suggests that fruit and vegetables could protect against bladder cancer by inhibiting the formation of DNA adducts.
Carcinogenesis 2000 Feb
PMID:White blood cell DNA adducts and fruit and vegetable consumption in bladder cancer. 1065 56


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