Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.1 (NADPH-diaphorase)
 3,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is an anti-tumour agent that has a highly selective toxicity to hypoxic cells. In this study we delineate the role of several different bioreductive enzymes in the metabolism of SR 4233 by two tumour cell lines HT 1080 (human fibrosarcoma) and SCCVII (mouse carcinoma). Enzyme kinetics demonstrates similar KM of HT 1080 and SCCVII cell sonicates and differing Vmax. Among all cofactors tested, NADPH was the most important one in reducing SR 4233 by both tumour cell sonicates. NADH was the second most important cofactor while hypoxanthine and N-methylnicotinamide were less involved in the reduction of SR 4233. Carbon monoxide inhibited the reduction by about 60% suggesting that cytochrome P-450 may play a major role in the reduction of SR 4233 under hypoxia in both SCCVII and HT 1080 cells. DT diaphorase is also involved, particularly in HT 1080 cells, in this drug reduction. The level of functional cytochrome P-450, cytochrome P-450 reductase activity and DT diaphorase activity in both cell lines were assayed. These enzyme levels were all higher in SCCVII cells than in HT 1080 cells. This result correlated the higher Vmax of SR 4233 reduction in SCCVII cells than in HT 1080 cells.
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PMID:Metabolism of the bioreductive cytotoxin SR 4233 by tumour cells: enzymatic studies. 843 60

Isolated monkey corpus cavernosum muscle strips contracted with prostaglandin F2 alpha and treated with prazosin responded to transmural electrical stimulation with frequency-related relaxations that were abolished by tetrodotoxin. The nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NNA) significantly attenuated but did not abolish the response; L-arginine reversed the inhibition. The neurogenic relaxation was not influenced in the strips treated with atropine or calcitonin gene-related peptide (CGRP)-(8-37), a CGRP-receptor antagonist, and those desensitized to vasoactive intestinal polypeptide (VIP) or pituitary adenylate cyclase-activating polypeptide (PACAP). Nerve fibers containing NADPH diaphorase were histochemically demonstrated in cavernous tissues. The relaxant response resistant to the NO synthase inhibitor was abolished by high K+ and tetrabutylammonium but was unaffected by glibenclamide, charybdotoxin, apamin, ouabain, SKF-525a, a cytochrome P-450 inhibitor, and oxyhemoglobin. It is concluded that neurogenic relaxations of monkey corpus cavernosum muscle is associated partly with NO released as a neurotransmitter and that other relaxing factor(s) possibly responsible for K+ channel opening also participates; however, the type of K+ channel involved is not determined. Acetylcholine, VIP, CGRP, PACAP, and the Na+ pump do not seem to be involved in the neurogenic relaxation.
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PMID:Monkey corpus cavernosum relaxation mediated by NO and other relaxing factor derived from nerves. 957 9

Diaphorase was studied as a possible oxidoreductase participating in NO production from some vasorelaxants. In the presence of NADH or NADPH, diaphorase can convert selected NO donors, glycerol trinitrate (GTN) and formaldoxime (FAL) to nitrites and nitrates with NO as an intermediate. This activity of diaphorase was inhibited by diphenyleneiodonium (DPI) (inhibitor of some NADPH-dependent flavoprotein oxidoreductases), while it remained uninhibited by NG-nitro-L-arginine methyl ester (inhibitor of NO synthase) 7-Ethoxyresorufin (inhibitor of cytochrome P-450 1A1 and cytochrome P-450 NADPH-dependent reductase) inhibited the conversion of GTN only. Existence of NO as an intermediate of the reaction was supported by results of electron paramagnetic resonance spectroscopy. In addition to its ability to affect the above mentioned NO donors, diaphorase was able to reduce 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) and thus to eliminate its NO scavenging effect. This activity of diaphorase could also be inhibited by DPI. The reaction of diaphorase with GTN and PTIO was not affected by superoxide dismutase (SOD) or catalase. Reaction of FAL with diaphorase was lowered with SOD by 38 % indicating the partial participation of superoxide anion probably generated by the reaction of diaphorase with NADH or NADPH. Catalase had no effect. Diaphorase could apparently be one of the enzymes participating in the metabolism of studied NO donors to NO. The easy reduction and consequent elimination of PTIO by diaphorase could affect its use as an NO scavenger in biological tissues.
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PMID:Diaphorase can metabolize some vasorelaxants to NO and eliminate NO scavenging effect of 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide (PTIO). 1558 29


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