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)

Groups of male Wistar rats were fed semi-synthetic diets containing 0, 200 or 500 mg indole-3-carbinol (13C)/kg for 2, 7, 14 or 28 days. After 2 days, P-450 activities were already induced, but the isoenzyme pattern induced was different in the liver and the small intestine. Hepatic P4501A1, P4501A2 and P4502B1 apoprotein levels were dose-relatedly enhanced, whereas in the small intestine induced levels of P4502B1 and P4501A1 were detected but P4501A2 was not induced. Pentoxy- and ethoxyresorufin dealkylation (PROD and EROD) were dose-relatedly enhanced in the liver (5- and 7-fold, respectively, in the higher dose group) as well as in the small intestine (8- and 13-fold, respectively, at 500 mg 13C/kg diet). Testosterone 16 alpha- and 16 beta-hydroxylation in the small intestine were enhanced (6-9-fold) from day 2 onwards, but in the liver these activities were only slightly enhanced from day 7 onwards. Thus, the major forms induced in the liver appear to be P4501A1, P4501A2, P4502B1 and, to a lesser extent, P4503A, whereas in the small intestine all of the effects that were found are associated with only one cytochrome P-450, P4502B1. After 2 days I3C (500 mg/kg) induced glutathione S-transferase in the liver (1.3-fold) and small intestine (1.5-fold). Hepatic glucuronyl transferase (GT1) was induced (about 1.6-fold) after 7, 14 and 28 days. DT-diaphorase was induced in the liver (2.7-fold) and small intestine (1.5-fold) after 14 days of exposure to 500 mg I3C/kg diet. Treatment of rat hepatocytes with indole-3-acetonitrile and 3,3'-diindolylmethane, but not I3C and indole-3-carboxaldehyde, enhanced EROD activity and halved testosterone 16 alpha- and 2 alpha-hydroxylation. All four indoles slightly induced glutathione S-transferase in cultured hepatocytes. Thus, the in vitro studies suggest that the in vivo effects of I3C have to be attributed to indole-condensation products, such as 3,3'-diindolylmethane, but not to I3C itself.
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PMID:Effects of indole-3-carbinol on biotransformation enzymes in the rat: in vivo changes in liver and small intestinal mucosa in comparison with primary hepatocyte cultures. 152 33

The effects of three acid condensation products of indole-3-carbinol (I3C), i.e. 3,3'-diindolylmethane (DIM), 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b"]tri-indole (CTI) and 2,3-bis[3-indolylmethyl]indole (BII), on cytochrome P450 and phase II enzymes were studied in primary cultures of rat and cynomolgus monkey liver cells. In rat hepatocytes all three indole derivatives dose-relatedly induced the ethoxyresorufin O-dealkylation (EROD) activity (to 24-fold) and 7 alpha-hydroxylation of testosterone (to 4-fold), whereas all three decreased the 16 alpha- and 2 alpha-testosterone hydroxylation (DIM to 60%, CTI and BII to a mere 5% of the control cells). Treatment of monkey hepatocytes with DIM and BII enhanced the EROD activity to 6- and 9-fold, respectively. Furthermore, BII decreased the 6 beta-hydroxylation of testosterone (to 60% of the untreated cultures) in monkey cells. Phase II enzymes were also affected. In rat hepatocytes DIM, CTI and BII enhanced DT-diaphorase (DTD) (= NAD(P)H-quinone reductase) activity, and DIM and BII the glucuronidation of 1-naphthol. In monkey cells BII only enhanced DTD, and no changes were observed in the glucuronidation of 1-naphthol after treatment with either DIM or BII. The indole derivatives did not affect glutathione S-transferase activity and sulfation of 1-naphthol in either rat or monkey hepatocytes. These results identify two novel acid condensation products of I3C, CTI and BII, as potent compounds in affecting biotransformation in rat as well as in monkey hepatocytes.
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PMID:Acid reaction products of indole-3-carbinol and their effects on cytochrome P450 and phase II enzymes in rat and monkey hepatocytes. 156 68

Three indole antioxidants were compared for their efficacy to inhibit lipid peroxidation, prevent chemical hepatotoxicity and induce enzyme systems involved in the biotransformation of xenobiotics. The dietary indolyl compound indole-3-carbinol (I-3-C), and the synthetic compounds 5,10-dihydroindeno[1,2-b]-indole (DHII) and 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) inhibited carbon tetrachloride (CCl4)-initiated lipid peroxidation in rat-liver microsomes, with the order of efficacy THII greater than DHII = butylated hydroxytoluene (BHT) much greater than I-3-C. Each of the indole compounds protected isolated rat hepatocytes against toxicity by CCl4, N-methyl-N'-nitro-N-nitrosoguanidine and methylmethanesulphonate (THII congruent to DHII much greater than I-3-C). In vivo administration of the indole compounds 1 hr before treatment with CCl4 protected against hepatotoxicity (THII greater than DHII greater than I-3-C). For the enzyme induction studies, phenobarbital and beta-naphthoflavone were used as standards, with corn-oil vehicle controls. The compounds were administered by gavage at 50 mg/kg body weight/day for 10 days. I-3-C produced increases in levels of hepatic cytochromes P-450 and ethoxyresorufin O-deethylase (EROD) activity, as well as in UDP-glucuronosyl transferase (UDPGT), glutathione S-transferase (GST), glutathione reductase (GSSG-Red) and quinone reductase. I-3-C produced decreased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. DHII produced increases in EROD, UDPGT, GST, GSSG-Red and quinone reductase, with decreases in NDMA-demethylase and GSH-Px activities. The only observed effect of THII was a modest induction of EROD activity. After treatment with the indole compounds for 10 days, I-3-C enhanced, while DHII diminished, CCl4-mediated 24-hr hepatotoxicity in rats. We conclude that DHII and THII are suitable candidates to develop further as potential chemoprotective and therapeutic agents for use in humans to treat disorders involving free radicals. THII has the greater radical scavenging efficacy, whereas DHII has the greater capacity to induce many different antioxidative enzymes.
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PMID:Chemoprotective and hepatic enzyme induction properties of indole and indenoindole antioxidants in rats. 187 67

The potency of indole-3-carbinol (I3C) to form condensation products under acidic aqueous conditions was studied. After identifying a known dimer, 3,3'-diindolylmethane (DIM), we elucidated the structures of two trimers also found in acid reaction mixtures: 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b"]tri-indole (CTI), and 2,3-bis[3-indolylmethyl] indole (BII). The formation of these indole oligomers was shown to be pH dependent. The highest amounts of DIM and BII were formed in aqueous solutions having a pH value ranging from 4 to 5. No CTI could be detected at pH values above 4.5. In rats that received an oral dose of I3C we could detect DIM and BII in gastric contents, stomach tissue, small intestine and liver. No CTI could be detected in vivo after oral exposure to I3C. In in vitro experiments, using rat hepatocytes, the cytochrome P-450IA1 apoprotein level, 7-ethoxyresorufin O-deethylation activity (EROD) and DT-diaphorase activity (DTD) were markedly enhanced by DIM and CTI as well as BII.
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PMID:Structure elucidation of acid reaction products of indole-3-carbinol: detection in vivo and enzyme induction in vitro. 195 58

Indole-3-carbinol (I-3-C) and 5,10-dihydroindeno[1,2-b]indole (DHII) have been shown to be protective against carbon tetrachloride and other chemicals that cause hepatic toxicity. In part, this protection appears to be afforded by the ability of these compounds to act as antioxidants, with DHII having much the greater efficacy. In order to understand the mechanisms of chemoprotection, as well as the potential for therapeutic and pharmaceutical use in humans, the antioxidants I-3-C and DHII were examined for their intrinsic acute toxicity, and their hepatic enzyme inducing properties in mice. The results were compared with those of the well characterized agent phenobarbital. Following treatment by gavage for 10 days with 50 mg compound/kg body weight, I-3-C produced modest (10-50%) increases in hepatic cytochrome P-450, aminopyrine N-demethylase, UDP-glucuronosyl transferase (UDPGT) and glutathione S-transferase (GST), and a four-fold increase in NAD(P)H: (quinone acceptor) oxidoreductase (quinone reductase) activity. DHII did not alter oxidative enzyme activities, but increased GST and UDPGT by about 50%, and quinone reductase over five-fold. In the acute toxicity studies, DHII produced no observable 24-hr acute toxicity up to 4 g/kg body weight, except for a slight decrease in haematocrit. However, I-3-C exhibited a dose-dependent toxicity above 100 mg/kg body weight, including a decrease in hepatic reduced glutathione after 2 hr and severe neurological toxicity, and the release of liver enzymes to the plasma at 24 hr. We conclude, on the basis of the superior antioxidation efficacy of DHII, its enzyme-inducing properties, and intrinsic toxicity, that DHII or cogeners thereof have great potential as chemoprotective or therapeutic agents. However, I-3-C does not have such potential.
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PMID:Intrinsic acute toxicity and hepatic enzyme inducing properties of the chemoprotectants indole-3-carbinol and 5,10-dihydroindeno[1,2-b]indole in mice. 204 Apr 85

DT-diaphorase (DTD) is a flavoprotein that catalyses the two-electron reduction of various redox dyes and quinones such as menadione and phylloquinone. It has been proposed that this enzyme may have a protective effect against cancer, as the two-electron reduction prevents the formation of toxic oxygen metabolites that may be generated as a result of the one-electron reduction catalysed by enzymes such as NADPH-cytochrome P-450 reductase. The effects of a purified diet supplemented with either 25% Brussels sprouts, phylloquinone (2.5 or 25 ppm) or 250 ppm indole-3-carbinol on hepatic and intestinal DTD activity in adult male Sprague-Dawley rats have been determined. One group was fed on the purified diet and dosed with 3-methylcholanthrene (20 mg/kg), 24 hr before being killed. Hepatic DTD activity was increased 3-fold in the indole-3-carbinol group, 4.4-fold in the sprouts-fed animals and 8.2-fold in the 3-methylcholanthrene-treated animals. Neither level of phylloquinone affected hepatic DTD activity. Intestinal DTD activity was increased 2.1-fold in the indole-3-carbinol group, 3.7-fold in the sprouts-fed animals and 4.3-fold in the 3-methylcholanthrene group. In animals given 25 ppm phylloquinone, intestinal enzyme activity was 60% of the control level, while no effect was noted in those given 2.5 ppm phylloquinone. Although increases in the activities of intestinal xenobiotic-metabolizing enzymes resulting from dietary influences are well documented, the increase in hepatic DTD activity seen in response to vegetable consumption has not been reported. The significance of these results in relation to the possible protective effects of dietary cruciferous vegetables against cancer is discussed.
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PMID:Dietary influences on rat hepatic and intestinal DT-diaphorase activity. 309 49

The effects of dietary administration of equimolar doses (5 mmol/kg body wt per day) of trimethylene oxide, trimethylene sulfide, coumaran, benzofuran, indole, and indole-3-carbinol on the activities of microsomal epoxide hydrolase and several other xenobiotic metabolizing enzymes were measured in the liver of female CD-1 mouse. Every compound, with the exception of indole, caused a significant increase (P less than 0.01) of the styrene oxide epoxide hydrolase activity over controls in hepatic microsomes. These results indicate that the enzyme activity is elevated in vivo by several heterocyclic compounds with strained bond angles to a nucleophilic hetero-atom. In addition, the ability of sulfur-containing trimethylene sulfide and nitrogen-containing indole-3-carbinol to elevate the enzyme activity indicates that the heterocyclic oxygen atom is not an absolute requirement for this effect. Data from the other xenobiotic metabolizing enzymes indicate that trimethylene oxide and trimethylene sulfide enhance the epoxide hydrolase activity rather specifically, while not affecting the activities of the other enzymes measured. While the oxygen-containing coumaran and benzofuran both increased the NADH: quinone reductase activity in hepatic cytosol, the nitrogen-containing indole and indole-3-carbinol did not. This indicated a specific requirement for the oxygen atom in elevating the quinone reductase activity, which was not the case for the elevation of microsomal epoxide hydrolase activity.
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PMID:Enhancement of epoxide hydrolase activity in hepatic microsomes of mice given heterocyclic compounds. 376 53

Induction of phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen. Since consumption of large quantities of fruit and vegetables is associated with a striking reduction in the risk of developing a variety of malignancies, it is of interest that a number of edible plants contain substantial quantities of compounds that regulate mammalian enzymes of xenobiotic metabolism. Thus, edible plants belonging to the family Cruciferae and genus Brassica (e.g., broccoli and cauliflower) contain substantial quantities of isothiocyanates (mostly in the form of their glucosinolate precursors) some of which (e.g., sulforaphane or 4-methylsulfinylbutyl isothiocyanate) are very potent inducers of phase 2 enzymes. Unexpectedly, 3-day-old sprouts of cultivars of certain crucifers including broccoli and cauliflower contain 10-100 times higher levels of glucoraphanin (the glucosinolate of sulforaphane) than do the corresponding mature plants. Glucosinolates and isothiocyanates can be efficiently extracted from plants, without hydrolysis of glucosinolates by myrosinase, by homogenization in a mixture of equal volumes of dimethyl sulfoxide, dimethylformamide, and acetonitrile at -50 degrees C. Extracts of 3-day-old broccoli sprouts (containing either glucoraphanin or sulforaphane as the principal enzyme inducer) were highly effective in reducing the incidence, multiplicity, and rate of development of mammary tumors in dimethylbenz(a)anthracene-treated rats. Notably, sprouts of many broccoli cultivars contain negligible quantities of indole glucosinolates, which predominate in the mature vegetable and may give rise to degradation products (e.g., indole-3-carbinol) that can enhance tumorigenesis. Hence, small quantities of crucifer sprouts may protect against the risk of cancer as effectively as much larger quantities of mature vegetables of the same variety.
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PMID:Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. 929 17

A range of potential chemoprotective agents, most of them natural dietary constituents, has been examined for ability to modulate both phase I (cytochrome P450 1A1, 1A2, 2B1/2, 2C11, 2E1, 3A, 4A) and phase II drug metabolizing enzymes (glutathione S-transferases, in particular subunits Yc2 and P, aflatoxin B1-aldehyde reductase and quinone reductase) in rat liver. In addition to assays of total enzyme activity and Western blots for individual isozymes, the ability of microsomes to metabolize aflatoxin B1, and of cytosols to conjugate aflatoxin B1 (AFB1)-epoxide to GSH and to produce AFB1-dialcohol, were measured. Induction of gamma-glutamyl transpeptidase activity was examined by histochemistry. Differing patterns of induction were observed, reflecting differences in the control of expression of the individual enzymes studied. Of the compounds examined, butylated hydroxytoluene, ethoxyquin, indole-3-carbinol and phenethyl isothiocyanate were the most potent bifunctional agents (inducing both phase I and II activities). Oltipraz, while only weakly inducing CYP1A2 and 2B1/2, was a potent inducer of phase II enzymes. Caffeic acid, garlic oil, sinigrin and propyl gallate all showed some ability to induce phase II enzymes. 4-Methyl catechol, alpha-tocopherol and red wine decreased certain phase I enzyme activities, while inducing total GST activity. Butylated hydroxytoluene, ethoxyquin, garlic oil and indole-3-carbinol induced gamma glutamyltranspeptidase in periportal hepatocytes. Particularly because of their ability to induce the detoxifying activities of glutathione S-transferase Yc2 and aldehyde reductase, butylated hydroxytoluene, ethoxyquin, indole-3-carbinol, oltipraz, phenethyl isothiocyanate and sinigrin will be effective blocking agents in rodents, if administered prior to AFB1. While these studies indicate the relative contributions of phase I and II metabolism in the overall protective effect in rat, care should be taken that a similar balance is achieved in man, and that relevant enzymes or iso forms are induced.
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PMID:Mechanism of action of dietary chemoprotective agents in rat liver: induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism. 932 68

Four glucosinolate derivatives were evaluated individually and as a mixture for their effects on hepatic P4501A (CYP1A), glutathione S-transferase (GST), quinone reductase (QR), glutathione reductase (G-Rd), and GSH levels. Doses of the derivatives were chosen to represent their relative abundance in Brussels sprouts. Adult male F344 rats received either corn oil (vehicle); one of the agents: indole-3-carbinol (I3C, 56 mg/kg), iberin (38 mg/kg), phenylethylisothiocyanate (PEITC, 0.1 mg/kg), or cyanohydroxybutene (crambene, 50 mg/kg); or all of the agents at the doses shown (as a mixture) given by gavage daily for 7 days. The mixture and I3C caused an 11- and 9.4-fold induction of CYP1A, respectively. Crambene and I3C each caused a 1.4-fold increase in GST, while the mixture caused a 2.5-fold increase. Crambene and I3C caused a 2.5- and 1.9-fold increase in QR, respectively. The mixture caused a 6.2-fold increase. Crambene, PEITC, and the mixture caused a 1.8-, 1.6-, and 2.0-fold increase in hepatic GSH levels, respectively. Crambene, I3C, iberin, and the mixture caused 1.3-, 1.4-, 1.2-, and 1.7-fold increases in G-Rd, respectively. In a second study the mixture was given at 60 and 20% of the original dose. CYP 1A, QR, G-Rd, and GST elevations were dose-dependent; GSH levels were not elevated. It is concluded that I3C and crambene are responsible for the majority of enzyme increases seen. A synergistic effect of I3C and crambene was evident on induction of GST and QR, but not on GSH, G-Rd, or P4501A.
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PMID:A comparison of the individual and collective effects of four glucosinolate breakdown products from brussels sprouts on induction of detoxification enzymes. 985 97


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