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)

In toxicology, it is of interest not only to assess enzyme levels and capacities for potential fluxes, but it is also useful to develop methods for determining actual concentrations and fluxes in the intact cell and organ. To this end, several noninvasive techniques have been developed over the years. Our interest has been largely in photometric techniques. Transmission spectrophotometry through solid organs permits monitoring of the cytochromes of the mitochondrial respiratory chain and cytochrome P-450 as well as other pigments of biological interest. Furthermore, the steady state level of catalase Compound I in liver provides information on rates of H2O2 production. These are in the nM to microM concentration range. More recently, the monitoring of photoemission from intact organs has been useful in toxicological problems. The major photoemissive species, singlet molecular oxygen and excited carbonyls, can now be monitored with good signal/noise ratio. Redox cycling of quinones and the generation of photoemissive species were studied in menadione metabolism. Inhibition of phase II led to a significant increase in the steady state level of singlet oxygen, as did the inhibition of two-electron reduction by using the inhibitor dicoumarol for DT diaphorase. Conversely, the induction of DT diaphorase by pretreatment with BHA protected by decreasing the level of reactive oxygen species.
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PMID:Intact organ spectrophotometry and single-photon counting. 330 3

1. The chemical reactivity of bromobenzene metabolite(s) responsible for its protein covalent binding was investigated by determining the effects of many chemical and enzymic probes on the metabolism and covalent binding of [3,5-3H]bromobenzene with rat liver microsomes in vitro. 2. Classical cytochrome P-450 enzyme inhibitors decreased both metabolism and binding in parallel, whereas scavenging agents for reactive oxygen species and free radicals exhibited little or no effect. Sulphur nucleophiles were extremely efficient in decreasing binding with little or no effect on metabolism. Reducing agents such as ascorbate and diaphorase decreased binding slightly more than metabolism. 3. UDP-Glucuronic acid inhibited neither metabolism nor binding, but all three mono-bromophenols decreased binding more than metabolism. Trichloropropene oxide was unique in decreasing metabolism more than binding. 4. The effects of ascorbate, glutathione, bisulphite and butylated hydroxytoluene (BHT) on metabolism and binding of five ortho-substituted bromobenzene derivatives (o-BrC6H4X; X = OCH3, CH3, Br, CF3, and CN) were similar to their effects on the metabolism and binding of bromobenzene. 5. Collectively these results support a major role for quinones as the reactive metabolites responsible for the majority of the protein covalent binding of bromobenzene and its ortho-substituted derivatives in microsomal systems in vitro.
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PMID:Effects of chemical and enzymic probes on microsomal covalent binding of bromobenzene and derivatives. Evidence for quinones as reactive metabolites. 340 Feb 72

This study was performed in order to study the response of epoxide hydrolases in different subcellular compartments of mouse liver to treatment with various compounds. Male C57BL/6 mice were treated with 31 different compounds--including traditional inducers of xenobiotic-metabolizing systems, liver carcinogens, stilbene derivatives, endogenous compounds and various other drugs and xenobiotics. The effects on liver somatic index; protein contents in 'mitochondria', microsomes and cytosol prepared from the liver; epoxide hydrolase activity towards trans- or cis-stilbene oxide in these three fractions; microsomal cytochrome P-450 content; cytosolic and 'mitochondrial' glutathione transferase activity and cytosolic DT-diaphorase activity were then determined. Cytosolic epoxide hydrolase activity was induced by chlorinated paraffins, di(2-ethylhexyl)phthalate and clofibrate and depressed by alpha-naphthylisothiocyanate, 3-methylcholanthrene, benzil and quercitin. Radial immunodiffusion revealed similar changes in the amount of enzyme protein present, except for two cases, where the increase in amount was larger; and the enzyme seems to be inhibited by benzil. Microsomal epoxide hydrolase activity was induced by these same compounds and several others as well, including dibenzoylmethane, butylated hydroxyanisole and polychlorinated biphenyls. 'Mitochondrial' epoxide hydrolase activity towards trans-stilbene oxide was not affected by those compounds which induced the cytosolic enzyme, but increased about two-fold after treatment with 2-acetylaminofluorene, DL-ethionine, aflatoxin B1 and phenobarbital. There does not seem to be any co-regulation of different forms of epoxide hydrolase in mouse liver. In general small effects were observed on liver weight and protein contents in the different subcellular fractions. Polychlorinated biphenyls were the most potent of the 8 compounds which induced cytochrome P-450, while butylated hydroxyanisole induced cytosolic glutathione transferase activity to the highest extent. 'Mitochondrial' glutathione transferase activity was most induced by certain of the stilbene derivatives. The most potent inducers of DT-diaphorase activity were 3-methylcholanthrene, polychlorinated biphenyls and dinitrotoluene.
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PMID:Hepatic levels of cytosolic, microsomal and 'mitochondrial' epoxide hydrolases and other drug-metabolizing enzymes after treatment of mice with various xenobiotics and endogenous compounds. 362 71

The present paper describes a marked induction of liver microsomal cytochrome P-450 and cytosolic DT-diaphorase to cause possible disorder of steroid homeostasis and promotion of carcinogenicity of 4-nitroquinoline N-oxide (4-NQO) in rats by pretreatment with 3,4,5,3',4'-pentachlorobiphenyl (PenCB) or 2,3,4,7,8-pentachlorodibenzofuran (PenCDF). The animals were sacrificed 5 days after the pretreatment. These induction experiments showed that 7 alpha-hydroxylation of both progesterone and testosterone in liver microsomes was selectively increased to a great extent, but hydroxylations at the 2 alpha-, 6 beta- and 16 alpha-positions were depressed, together with 5 alpha-reduction. From the same microsomes, three of the strongly induced P-450 isozymes, i.e., high- and low-spin P-448s and P-452, were purified. The last isozyme was most responsible for 7 alpha-hydroxylation of testosterone. The pretreatment, also increased activity of DT-diaphorase and reduction of 4-NQO about 10-fold in liver 9000g supernatants. This reduction of 4-NQO was solely catalyzed by DT-diaphorase and the only product was 4-hydroxylaminoquinoline N-oxide, a proximate carcinogen, indicating that the pretreatment strongly increased production of a proximate carcinogen from 4-NQO. Such an enhancement of the metabolic activation of 4-NQO by the pretreatment was also observed to some extent in the lung and the skin. Persistency of PenCB and PenCDF in the liver of rats was also discussed.
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PMID:Inductive effect on hepatic enzymes and toxicity of congeners of PCBs and PCDFs. 392 54

Since the cure of solid tumors is limited by the presence of cells with low oxygen contents, we have approached the development of treatment regimens and of new drugs for these tumors by investigating agents which are preferentially bioactivated under hypoxia. Major emphasis has been directed at studying the mode of action of the mitomycin antibiotics, as bioreductive alkylating agents. Using primarily the EMT6 mouse mammary carcinoma as a solid tumor model, we have found that mitomycin C and porfiromycin are preferentially toxic to cells with low oxygen contents. The mitomycin analog BMY-25282 is more toxic to hypoxic cells than are mitomycin C and porfiromycin; however, unlike these antibiotics, BMY-25282 is preferentially toxic to well-oxygenated cells. With these three mitomycins, we have observed a correlation between cytotoxicity to hypoxic cells, the rate of generation of reactive products, and the redox potentials of the drugs. Investigations of the enzymes in EMT6 cells that could possibly activate mitomycin C have revealed that cytochrome P-450 and xanthine oxidase are not present in measurable quantities and therefore are not responsible for activation of mitomycin C. Activities representative of NADPH-cytochrome c reductase and DT-diaphorase are present in these neoplastic cells. Comparison of these enzymatic activities in EMT6, CHO, and V79 cells with the rate of generation of reactive products under hypoxia shows a direct correlation between these two parameters, but there is no quantitative correlation between these two parameters and the amount of cytotoxicity. Use of purified NADPH-cytochrome c reductase and inhibitors of this enzyme demonstrated that NADPH-cytochrome c reductase can activate mitomycin C, but that it is probably not the only enzyme participating in this bioactivation in EMT6 cells. The DT-diaphorase inhibitor dicoumarol was employed to show that this enzyme is not involved in the activation of mitomycin C to a cytotoxic agent. Instead, DT-diaphorase appears to metabolize mitomycin C to a nontoxic product. This property has been exploited to develop a new treatment regimen for solid tumors. Using X-rays to eliminate well oxygenated cells of a solid tumor implant of the EMT6 carcinoma, we have found that the combination of dicoumarol plus mitomycin C is more toxic to hypoxic tumor cells in vivo than mitomycin C alone. Furthermore, knowledge of the biochemical mechanism of mitomycin C activation permits a prediction of which tumors can best be treated with this combination of drugs by measuring enzymatic activities in biopsy specimens.
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PMID:Chemotherapeutic attack of hypoxic tumor cells by the bioreductive alkylating agent mitomycin C. 393 22

Oral administration of Prudhoe Bay crude or Hibernia crude to nestling herring gulls increased the hepatic cytochrome P-450 content 4-fold. Concomitantly, there was an increase in various mixed-function oxidase and phase II enzyme activities. 7-Ethoxyresorufin O-deethylase was elevated 19-fold, benzo(a)pyrene 3-hydroxylase 6-fold, aniline hydroxylase 3-fold, and aminopyrine N-demethylase and uridine diphosphate glucuronyl transferase 2-fold. There was no change in reduced glutathione S-transferase activity. Renal mixed-function oxidase activities were also elevated. Herring gull livers contained very low levels of DT-diaphorase activity which was inducible 3- to 5-fold by oil administration.
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PMID:Effects of ingestion of hibernia and Prudhoe Bay crude oils on hepatic and renal mixed function oxidase in nestling herring gulls (Larus argentatus). 396 42

The cytotoxicity of menadione (2-methyl-1,4-naphthoquinone) had been investigated using primary cultures of rat hepatocytes. Menadione was found to induce DNA strand breaks which were actively repaired by the cells. Dicoumarol, an inhibitor of DT diaphorase, did not potentiate menadione-induced DNA strand breaks. Neither had metyrapone, an inhibitor of cytochrome P-450 dependent monooxygenases, any effect on the extent of DNA damage. Covalent binding of menadione metabolite(s) to DNA was detected in the cultured hepatocytes and, in addition, hepatic microsomes were also found to metabolize menadione to DNA-binding products. The extent of binding of menadione to DNA in vitro, was markedly decreased by inclusion of the hepatic cytosol fraction, or reduced glutathione, in the incubations. In the presence of dicoumarol, menadione was also found to induce cell membrane damage. It also caused a rapid loss in cellular glutathione which was augmented by the presence of dicoumarol. The results suggest that both the cell membrane damage and DNA damage induced by menadione are mediated by one-electron reduction of the quinone to free radical intermediate(s). DT diaphorase appears to protect the cell from membrane damage, whereas reduced glutathione may have an important role in the prevention of DNA damage.
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PMID:Induction of DNA damage by menadione (2-methyl-1,4-naphthoquinone) in primary cultures of rat hepatocytes. 620 38

Reductive metabolism of carcinogenic 1-nitropyrene by rat liver microsomes and reconstituted cytochrome P-450 systems was investigated. Under the nitrogen atmosphere, 1-aminopyrene was the only detected metabolite of 1-nitropyrene. The reductase activity in liver 105,000 X g supernatant fraction was ascribed to DT-diaphorase, aldehyde oxidase, and other unknown enzyme(s) from the results of cofactor requirements and inhibition experiments. The microsomal reductase activity was inhibited by oxygen, carbon monoxide, 2,4-dichloro-6-phenylphenoxyethylamine, and n-octylamine. Flavin mononucleotide markedly enhanced the activity, and 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride also enhanced it, but slightly. The microsomal activity was induced by the pretreatment of rats with 3-methylcholanthrene, sodium phenobarbital, or polychlorinated biphenyl, and the increments of the activity correlated well with those of the specific contents of cytochrome P-450 in microsomes. The reductase activity could be reconstituted by NADPH-cytochrome P-450 reductase and forms of cytochrome P-450 purified from liver microsomes of polychlorinated biphenyl-induced rats. Among four forms of cytochrome P-450 examined, an isozyme P-448-IId which showed high activity in hydroxylation of benzo(a)pyrene catalyzed most efficiently the reduction of 1-nitropyrene. The results of this study indicate the central role of cytochrome P-450 in the reductive metabolism of 1-nitropyrene in liver microsomes.
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PMID:Participation of cytochrome P-450 in reductive metabolism of 1-nitropyrene by rat liver microsomes. 643 May 44

Hypoxic cells of solid tumors are difficult to eradicate by X-irradiation or chemotherapy; as an approach to this problem, our laboratories are investigating the effects of the bioreductive alkylating agent mitomycin C (MC) on hypoxic cells. This antibiotic was preferentially toxic to EMT6 mouse mammary tumor cells and V79 Chinese hamster lung fibroblasts under hypoxic conditions, but it was equitoxic to Chinese hamster ovary cells in the presence and absence of oxygen. All cell lines catalyzed the formation of reactive metabolites under hypoxic conditions and contained NADPH:cytochrome c reductase and DT-diaphorase, two enzymes which may be responsible for the cellular activation of MC. Although a correlation existed between enzymatic activities and the formation of reactive metabolites from MC, there was no correspondence between these parameters and the degree of cytotoxicity expressed by MC under hypoxic conditions. Purified NADPH:cytochrome c reductase reduced MC in the absence of oxygen, with addition of cytochrome P-450 enhancing, but not participating directly in, the reduction reaction. Addition of NADP+ to cell sonicates substantially reduced NADPH:cytochrome c reductase activity, while the formation of reactive metabolites was affected only slightly; converse results were observed using mersalyl. Exposure of cell sonicates to dicumarol inhibited DT-diaphorase activity, while the rate of formation of reactive metabolites of MC was enhanced. The findings suggest that NADPH:cytochrome c reductase and some as yet to be identified enzyme(s) are important for the reductive activation of MC. DT-diaphorase and cytochrome P-450 are not directly involved in the activation of MC, but they appear to modulate the degree of activation to reactive species, which are presumably responsible for the observed cytotoxicity.
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PMID:Role of NADPH:cytochrome c reductase and DT-diaphorase in the biotransformation of mitomycin C1. 643 71

The mutagenicity of various quinones, a class of compounds widely distributed in nature, is demonstrated in the Salmonella TA104 tester strain. The metabolic pathways by which four quinones, menadione, benzo[a]pyrene 3,6-quinone, 9,10-phenanthrenequinone, and danthron, caused mutagenicity in this test system were investigated in detail as were the detoxification pathways. The two-electron reduction of these quinones by NAD(P)H-quinone oxidoreductase (DT-diaphorase) was not mutagenic, whereas the one-electron reduction, catalyzed by NADPH-cytochrome P-450 reductase, was mutagenic, except for danthron, which was only slightly mutagenic. The mutagenicity of the quinones via this pathway was found to be attributable to the generation of oxygen radicals. The cytochrome P-450 monooxygenase also played a significant role in the detoxification and bioactivation of these quinones. For example, phenanthrenequinone was converted to a nonmutagenic metabolite in a cytochrome P-450-dependent reaction, whereas danthron was converted to a highly mutagenic metabolite. These studies show the complexity of metabolic pathways involved in the mutagenicity of quinones.
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PMID:Mutagenicity of quinones: pathways of metabolic activation and detoxification. 658 3


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