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)

The formation of benzo[a]pyrene (BP)-3,6 quinol glucuronides in liver microsomes in the presence of UDP-glucuronic acid and NAD(P)H appears to occur by a sequence of three reactions: BP-3,6-quinone----BP-3,6 hydroquinone----BP-3,6-quinol monoglucuronide----BP-3,6-quinol diglucuronide. This conclusion is based on the following results. Incubations with [14C]BP-3,6-quinone or UDP-[14C]glucuronic acid and analysis of the samples by TLC established the existence and identity of the two BP-3,6-quinol glucuronides which exhibit different fluorescence spectra. The nature of the monoglucuronide, i.e., a quinol and not a semiquinone glucuronide, was suggested by the finding that the rate of diglucuronide formation was the same with or without NAD(P)H provided that a sufficient amount of monoglucuronide had been formed prior to oxidation of the nucleotides. Furthermore, BP-3,6-quinol monoglucuronides can serve as substrates in the formation of diglucuronides. The ratio between the decrease in monoglucuronides and the formation of diglucuronides was found to be close to 1, suggesting that the conversion of the monoglucuronide of BP-3,6-quinol to the diglucuronide is also catalyzed by UDP-glucuronosyltransferase. However, great differences in the pattern of induction of mono- and diglucuronide formation indicate that two different UDP-glucuronosyltransferases are involved. The yield of BP-3,6-quinol glucuronides with NADH relative to NADPH and the increase in glucuronide formation observed in the presence of cytosolic DT-diaphorase (NAD(P)H-quinone oxidoreductase) are discussed with regards as to whether DT-diaphorase plays an important role as a BP-3,6-quinone reductase in the formation of BP-3,6-quinol glucuronides compared to other NAD(P)H-oxidizing flavoproteins.
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PMID:Formation of benzo[a]pyrene-3,6-quinol mono- and diglucuronides in rat liver microsomes. 401 1

The biochemical properties of putative preneoplastic hepatocyte nodules as they relate to the metabolism of xenobiotics have been reviewed briefly. A common pattern with low phase I components and elevated phase II components appears evident. The phase I components included microsomal cytochromes P-450 in composite and four different mixed function oxygenase activities. The activities in the nodules were 50% or less of the control values. The phase II components included glutathione, glutathione S-transferases and UDP-glucuronyl transferase 1 and showed two- to five-fold elevations. In addition, activities of microsomal epoxide hydrolase, cytosolic DT-diaphorase, and gamma-glutamyl transferase were all elevated in nodules. The possible significance of this biochemical pattern in analyzing the diversity of biochemical expressions of cancer, in the mechanism of cancer development, and in understanding the suggested role of physiological adaptation in carcinogenesis is discussed.
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PMID:The biochemistry of preneoplastic liver: a common metabolic pattern in hepatocyte nodules. 638 Jun 87

Although the mechanisms responsible for chemically induced oxidative stress are under intense investigation, little is known about the effects of prooxidant chemicals on the expression of drug-metabolizing enzymes. We examined the effects of diquat (0.1 mmol/kg, ip) and ciprofibrate (0.025% w/w, diet), chemicals which induce oxidative stress via different biochemical mechanisms, on the steady-state messenger RNA (mRNA) levels of six cytochrome P450 enzymes, seven glutathione S-transferase (GST) isoenzymes, UDP-glucuronosyl transferase 1-06 (UGT1*06), gamma-glutamylcysteine synthetase (gamma GCS), NADP(H):quinone oxidoreductase (quinone reductase), Cu/Zn superoxide dismutase (SOD), catalase, and 18S ribosomal RNA in the livers of male Sprague-Dawley rats. Effects of chemical treatments on mRNA levels were compared to changes in catalytic activities for selected enzymes. Ciprofibrate treatment selectively decreased CYP1A2 mRNA expression, whereas both chemicals suppressed CYP3A2 mRNA expression. CYP4A1 mRNA expression and lauric acid hydroxylase activities were induced by ciprofibrate treatment, whereas diquat treatment moderately increased CYP4A1 mRNA levels without affecting lauric acid hydroxylase activities. The steady-state mRNA levels encoding constitutively expressed GST isozymes (Ya1, Ya2, Yb1, Yb2, and Yc1) were decreased by diquat exposure, and the mRNA encoding four of the five constitutively expressed GSTs (Ya1, Ya2, Yb1, and Yc1) were also decreased by ciprofibrate treatment. Nonconstitutively expressed or low constitutively expressed genes (CYP1A1, CYP2B1, CYP2B2, GST Yc2, GST Yf, and UGT1*06) were not induced by exposure to the prooxidants. Changes in isozyme-specific catalytic activities were more consistent with the observed changes in mRNA expression for the GSTs than for the P450s. Both treatments had inhibitory effects on hepatic GSH biosynthesis by decreasing gamma GCS large-subunit mRNA expression, gamma GCS catalytic activities, and hepatic GSH concentrations. Cu/Zn SOD and quinone reductase mRNA levels were increased after ciprofibrate exposure, whereas Cu/Zn SOD mRNA expression was decreased in the diquat-treated animals. The results of this study indicate that diquat and ciprofibrate can decrease the expression profile of a number of phase I, phase II, and antioxidant enzymes and inhibit GSH biosynthesis. These effects may involve the pretranslational loss of hepatic mRNAs, possibly due to accelerated production of reactive oxygen species.
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PMID:The effects of diquat and ciprofibrate on mRNA expression and catalytic activities of hepatic xenobiotic metabolizing and antioxidant enzymes in rat liver. 767 60

The glucosinolate hydrolysis product 1-isothiocyanato-3-(methylsulfinyl)-propane (IMSP), also known as iberin, is consumed in the average human (US) diet at approximately 1 mumol/kg/day. The chemoprotective effects observed with the consumption of cruciferous vegetables may be due to the presence of specific glucosinolate hydrolysis products either within the crucifers, or formed after ingestion of the crucifers. The mechanism of chemoprotection may be through selective induction of components of Phase II xenobiotic metabolizing enzymes. The influence of repeated administration of low concentrations of IMSP by gavage on components of Phase I and Phase II xenobiotic metabolizing systems was examined in the liver and small intestine of male Fischer 344 rats. Doses of 1, 10 and 100 mumol IMSP/kg, administered by gavage for 7 days, did not alter weight gain, or hepatic and renal weights, relative to body weight, and did not cause any histological lesions. Intestinal glutathione S-transferase (GST) activity and NAD(P)H:quinone reductase (QR) activities were significantly elevated to 3.1 and 8.1 times control values, respectively, at the 100 mumol/kg dose only. The administration of IMSP at 1, 10 or 100 mumol/kg had no significant effect on hepatic Phase I enzymes activities (cytochrome P-450 concentrations, ethoxycoumarin O-deethylase [ECD] and aminopyrine N-demethylase [AND] activities) or Phase II enzyme activities (GST, QR and UDP-glucuronosyltransferase [UDP-GT] activities towards 1-naphthol or 4-hydroxybiphenyl), at any of the doses tested and no effect on intestinal enzyme activities at doses below 100 mumol IMSP/kg. It is concluded that IMSP does not have a significant influence on induction of the Phase I or Phase II xenobiotic metabolizing enzymes in rats when tested at doses approximating those found in the human diet.
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PMID:Effects of 1-isothiocyanato-3-(methylsulfinyl)-propane on xenobiotic metabolizing enzymes in rats. 822 30

It has been reported that several naturally occurring and related synthetic organosulfur compounds exert chemopreventive effects in several target organs in rodent models. The chemopreventive actions of 40 and 80% maximum tolerated doses (MTD) of organosulfur compounds, namely anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine, administered in AIN-76A diet, on azoxymethane (AOM)-induced neoplasia were investigated in male F344 rats. Also, the effects of these agents on the activities of phase II enzymes, namely glutathione S-transferase (GST), NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase, in the liver and colonic mucosa and tumors were assessed. The MTD levels of anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine were determined in male F344 rats and found to be 250, 250, 1500, and 1500 ppm, respectively. At 5 weeks of age, animals were fed the control diet (AIN-76A) or experimental diets containing 40 or 80% MTD levels of each test agent. All animals in each group, except those allotted for vehicle (saline) treatment, were administered AOM s.c. at a dose rate of 15 mg/kg body weight once weekly for 2 weeks. All animals were necropsied during week 52 after the second AOM injection. Colonic mucosal and tumor and liver enzyme activities were measured in animals fed 80% MTD levels of each test agent. Colon tumors were subjected to histopathological evaluation and classified as invasive or noninvasive adenocarcinomas. Colon tumor incidence (percentage of animals with tumors) and tumor multiplicity (tumors/animal) were compared among various dietary groups. The results indicated that administration of 200 ppm (80% MTD) anethole trithione significantly inhibited the incidence and multiplicity of both invasive and noninvasive adenocarcinomas, whereas feeding of 100 ppm (40% MTD) anethole trithione or 100 (40% MTD) or 200 ppm (80% MTD) diallyl disulfide suppressed only invasive adenocarcinomas of the colon. Although diets containing N-acetylcysteine and taurine inhibited colon tumor multiplicity, the effect was somewhat marginal. GST, NAD-(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase activities in colonic mucosa and tumor and liver were significantly elevated in animals fed anethole trithione or diallyl disulfide, compared to those fed the control diet. N-Acetylcysteine and taurine slightly but significantly increased only the GST activity in the liver. Although other mechanisms are not excluded, inhibition of AOM-induced colon carcinogenesis by anethole trithione and diallyl disulfide may be associated, in part, with increased activities of phase II enzymes such as GST, NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase in the liver and colon.
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PMID:Chemoprevention of colon carcinogenesis by organosulfur compounds. 833 52

Exposure of rodents or their cells in culture to low doses of a wide variety of chemical agents, many of which are electrophiles, evokes a coordinated metabolic response that protects these systems against the toxicity (including mutagenicity and carcinogenicity) of higher doses of the same or other electrophiles. This response involves enhanced transcription of Phase 2 enzymes: glutathione transferases, NAD(P)H:quinone reductase, UDP-glucuronsyltransferases, and epoxide hydrolase, as well as the elevation of intracellular levels of reduced glutathione. We suggest that this cellular adaptation, which occurs in the liver and many peripheral tissues, be designated as the "Electrophile Counterattack" response. Seven families of highly diverse chemical agents that elicit this response include: oxidatively labile diphenols and quinones; Michael reaction acceptors (olefins conjugated to electron-withdrawing groups); isothiocyanates; organic hydroperoxides; vicinal dimercaptans; trivalent arsenicals; heavy metals (HgCl2, CdCl2) as well as mercury derivatives with high affinities for sulfhydryl groups; and 1,2-dithiole-3-thiones. An analysis of the molecular mechanisms of these enzyme inductions was carried out by transient expression in hepatoma cells of a plasmid containing a 41-bp enhancer element derived from the 5'-upstream region of the mouse glutathione transferase Ya gene, and the promoter region of this gene, linked to a human growth hormone reporter gene. The concentrations of 28 inducers (belonging to the seven chemical classes) required to double growth hormone production in this system spanned a range of four orders of magnitude and were closely and linearly correlated with the concentrations of the same compounds required to double the specific activity of quinone reductase in murine hepatoma cells. We therefore conclude that the regulation of these Phase 2 enzymes (and possibly also that of glutathione synthesis) by all of these inducers is mediated by the same enhancer element that contains AP-1-like sites. Similar enhancer sequences are present in the rat glutathione transferase Ya gene, and in the upstream regulatory regions of the quinone reductase genes of rat and human liver.
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PMID:The electrophile counterattack response: protection against neoplasia and toxicity. 835 13

In order to study the effects of trans-anethole and eugenol on drug-metabolizing enzyme activities in vivo, male Wistar rats were treated by gavage with trans-anethole (125 or 250 mg/kg body weight) or eugenol (250, 500 or 1000 mg/kg body weight) daily for 10 days. In liver microsomes and cytosol various phase-I and phase-II biotransformation enzyme activities were determined. No effect on total cytochrome P-450 content in liver microsomes from rats treated with eugenol or trans-anethole was observed. Administration of 1000 mg eugenol/kg body weight, but not the lower doses, significantly increased cytochrome P-450-dependent 7-ethoxy-resorufin O-deethylation (EROD) and 7-pentoxyresorufin O-depentylation (PROD); administration of trans-anethole (125 or 250 mg/kg body weight) did not alter EROD and PROD activities. In rat liver cytosol, UDP-glucuronyl transferase (GT) activity towards the substrate 4-chlorophenol was significantly increased in all treated rats, and activity towards 4-hydroxybiphenyl as substrate was significantly increased in rats treated with 250 mg trans-anethole/kg or with 500 or 1000 mg eugenol/kg. DT-diaphorase (DTD) activity was only significantly enhanced in the liver cytosol of rats treated with trans-anethole at 250 mg/kg body weight. Enhancement of cytosolic glutathione S-transferase (GST) activity towards 1-chloro-2,4-dinitrobenzene was found for all eugenol- and trans-anethole-treated rats. In addition, significantly increased levels of GST subunit 2 were measured by HPLC in the liver cytosol of rats treated with eugenol (500 or 1000 mg/kg body eight) or trans-anethole (250 mg/kg body weight). It is concluded that both eugenol and trans-anethole preferentially induced phase II biotransformation enzymes in rat liver in vivo.
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PMID:Effects of the naturally occurring alkenylbenzenes eugenol and trans-anethole on drug-metabolizing enzymes in the rat liver. 840 40

We have demonstrated previously that musk xylene, a non-mutagenic carcinogen, is a novel and specific inducer of CYP1A2 in rats (Iwata et al., Biochem Biophys Res Commun 184: 149-153, 1992). In the present study, the effects of musk xylene (50, 100 or 200 mg/kg body weight, i.p., for 5 consecutive days) on both Phase I and Phase II metabolizing enzymes in rat liver were investigated further and more completely. Among the mixed-function oxidases monitored, 7-ethoxycoumarin deethylase and 7-pentoxyresorufin depentylase activities were increased at all dose levels from 1.6- to 1.7-fold and 2.6- to 3.1-fold, respectively. Benzo[a]pyrene hydroxylase activity was increased significantly at only the 200 mg/kg dose level of musk xylene (1.5-fold). Regarding Phase II enzymes, activities of both cytosolic DT-diaphorase and glutathione S-transferase (GST) were increased up to 2.0- to 2.4-fold by musk xylene in a dose-dependent manner. Western blot analysis revealed that the changes in these activities were caused by increases in the amounts of DT-diaphorase and GST Ya subunit. Microsomal UDP-glucoronyltransferase (UDPGT) activity assayed with p-nitrophenol as substrate was increased 1.6- to 2.0-fold. These results show that musk xylene induces both Phase I cytochrome P450 mixed-function oxidase (CYP1A2 specific) and Phase II metabolizing enzyme systems (DT-diaphorase, GST Ya subunit and UDPGT) in rat liver.
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PMID:An unusual profile of musk xylene-induced drug-metabolizing enzymes in rat liver. 848 5

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], a substituted 1,2-dithiole-3-thione, protects against the acute and chronic toxicities of many xenobiotics and prevents chemically induced carcinogenicity in several target organs of rodents. The effects of dietary oltipraz, fed during the initiation and postinitiation stages, on azoxymethane-induced colon carcinogenesis and on the levels of several detoxifying enzymes, namely, glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities, were studied in male F344 rats. At 5 weeks of age, groups of animals were fed the control diet (modified AIN-76A diet) or a diet containing 200 ppm (40% maximum tolerated dose) of oltipraz. At 7 weeks of age, all animals except those in the vehicle (normal saline solution)-treated groups were given two weekly s.c. injections of azoxymethane at a dose of 15 mg/kg body weight. Three days after the second injection of azoxymethane, the groups of animals fed the oltipraz diet were transferred to the control diet (termed the initiation period) and the groups of animals receiving the control diet were transferred to the oltipraz diet (termed the postinitiation period). All groups were continued on this regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Intestinal tumors were evaluated histopathologically using routine procedures. Liver, colonic mucosa, and tumors were analyzed for glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities. The results indicate that oltipraz administered during the initiation stage significantly inhibited the incidence and multiplicity of invasive adenocarcinomas of the colon (P < 0.001), as well as the multiplicity of invasive and noninvasive adenocarcinomas (P < 0.01). Feeding of oltipraz during the postinitiation phase completely suppressed the formation of invasive adenocarcinomas (P < 0.0001) and significantly inhibited the formation of noninvasive and total adenocarcinomas, as well as the multiplicity (tumors/tumor-bearing animal, P < 0.001). Furthermore, oltipraz significantly suppressed the tumor volume when administered during the initiation phase (> 80%) or the postinitiation (> 93%) phase. Animals fed the oltipraz diet during the postinitiation stage showed increased levels of glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities (2-6-fold). Although the precise mechanism by which oltipraz inhibits colon tumor initiation and/or promotion remains to be elucidated, it is likely that the effect during the initiation stage may be due to an alteration of carcinogen metabolism.
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PMID:Chemopreventive effect of oltipraz during different stages of experimental colon carcinogenesis induced by azoxymethane in male F344 rats. 849 12

The effects of aging on the activities of drug-metabolizing enzymes and antioxidant enzymes were studied in male and female White-Footed mice (Peromyscus leucopus) at ages of 6, 8, 12, 18, 24, 30, 36, and 48 months. Male mice had significantly higher liver microsomal cytochrome P450 (P450) content and NADPH:cytochrome P450 oxidoreductase (P450 reductase) activities than females at all age groups. Many of the P450-dependent enzyme activities were also generally higher in males. Female mice showed age-dependent decreases in P450 content and the activities of P450 reductase, pentoxyresorufin O-dealkylase (PROD) and N-nitrosodimethylamine demethylase (NDMAd) in the liver from 6 to 24 months; while, the males showed an age-dependent decrease only for the liver PROD activity from 6 to 24 months. The old males (30-month old) appeared to have significantly higher activities for 6 beta-, 2 beta-, 16 alpha- and 16 beta-testosterone and androstenedione formation than the middle-aged (6- to 18-month old) and very old (48-month old) males. Females showed age-dependent decreases for the formation of 6 beta-, 2 beta-, 16 alpha- and 16 beta-testosterone in liver microsomes from 6 to 24 months. Lung microsomes from 6- and 8-month old males had much higher activities of ethoxyresorufin O-deethylase (EROD) and PROD than older males. The total NNK alpha-hydroxylation activities changed in the same pattern as lung microsomal EROD and PROD activities in both male and female mice. The activities of several phase II drug-metabolizing enzymes: glutathione S-transferase (GST), DT-diaphorase, sulfotransferase and UDP-glucuronosyl-transferase (UDPGT) did not show any significant age-dependent changes, with the possible exception that the GST activity in males decreased from 18 to 36 months. Males had about 3-fold higher UDPGT activities than females among all age groups. Glutathione peroxidase activities were drastically lower in old and very old males, and 6 to 24 months old males had significantly higher activities than the corresponding females. In females, superoxide dismutase activities decreased linearly to extremely low levels as mice aged. Catalase activities showed a tendency for increase with age in males. In conclusion, some P450-dependent activities and antioxidant enzymes, but not phase II drug-metabolizing enzymes, showed age-dependent changes; and most of these changes occur from 6 to 24 months. The demographic attributes of the White-Footed mouse are well-suited for physiological and biochemical studies of aging and can complement the more standard laboratory mouse model with its typical two year life span.
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PMID:Age- and gender-related variations in the activities of drug-metabolizing and antioxidant enzymes in the white-footed mouse (Peromyscus leucopus). 849 97


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