Nicotinamide adenine dinucleotide phosphate inhibition

Mitomycin (mitomycin C, Mitocin-C, Mutamycin) is an antibiotic that is derived from a species of Streptomyces. It is sometimes classified as an alkylating agent because it can covalently bind to and cross-link DNA. Mitomycin is thought to inhibit DNA synthesis through its abihty to alkylate double-strand DNA and bring about interstrand cross-hnking. There is evidence that enzymatic reduction by a reduced nicotinamide-adenine dinucleotide phosphate (NADPH) dependent reductase is necessary to activate the drug. 

I I 3. The answer is c. (Hardman, pp 1243-1247.) Antimetabolites of folic acid such as methotrexate, which is an important cancer chemotherapeutic agent, exert their effect by inhibiting the catalytic activity of the enzyme dihydrofolate reductase. The enzyme functions to keep folic acid in a reduced state. The first step in the reaction is the reduction of folic acid to 7,8-dihydrofolic acid (FH2), which requires the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). The second step is the conversion of FH2 to 5,6,7,8-tetrahydrofolic acid (FH ). This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADH) or NADPH. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thymidylate. The affinity of methotrexate for dihydrofolate reductase is much greater than for the substrates of folic acid and FH2. The action of... 

Metabolism of ethanol by alcohol dehydrogenase and the microsomal ethanol-oxidizing system (MEOS). Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by fomepizole and disulfiram, respectively. NAD +, nicotinamide adenine dinucleotide NADPH, nicotinamide adenine dinucleotide phosphate. 

Triazine (e.g., atrazine, simazine) and substituted urea (e.g., diuron, monuron) herbicides bind to the plastoquinone (PQ)-binding site on the D1 protein in the PS II reaction center of the photosynthetic electron transport chain. This blocks the transfer of electrons from the electron donor, QA, to the mobile electron carrier, QB. The resultant inhibition of electron transport has two major consequences (i) a shortage of reduced nicotinamide adenine dinucleotide phosphate (NADP+), which is required for C02 fixation and (ii) the formation of oxygen radicals (H202, OH, etc.), which cause photooxidation of important molecules in the chloroplast (e.g., chlorophylls, unsaturated lipids, etc.). The latter is the major herbicidal consequence of the inhibition of photosynthetic electron transport. 

Time-dependent inhibition should be examined. A 30-minute preincubation (i.e., with nicotinamide adenine dinucleotide phosphate (NADPH) enzyme, and drug candidate prior to addition of the probe substrate) is recommended. 

The enzyme dihydrofolate reductase (DHFR) catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH) reduction of folate to dihydrofolate and tetrahydrofolate, the class of cofactors used in the biosynthesis of thymidylate and hence DNA. Inhibition of DHFR prevents cell growth and kills cells, so... 

Superoxide production from paraquat in a pig pulmonary microvascular endotheUal cell suspension was demonstrated by Tampo et al. (1999) using 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazol[l,2-a]pyrazin-3-one, a chemiluminescence probe, to detect superoxide anions. Increased rates of superoxide production from paraquat, which were sensitive to superoxide dismutase, required the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) in the reaction medium, and occurred instantaneously after the addition of NADPH, which is impermeable to cell membranes. NADH as an electron donor was not as effective, and xanthine or succinate had no influence. Paraquat was anaerobically reduced in the presence of NADPH and 2-methyl-6-(p-metho-xyphenyl) - 3,7 - dihydroimidazol[l,2 - ajpyrazin- 3 -one to yield a one-electron reduced radical, and the reduction was inhibited by NADP". Diphenyleneio-donium, an inhibitor of flavoprotein reductase, also markedly inhibited both paraquat reduction and superoxide production. 

Furthermore, Ganji et al. (2009) showed that in cultured human aortic endothelial cells, niacin increased nicotinamide adenine dinucleotide phosphate [NAD(P)H] levels by 54% and reduced glutathione (GSH) by 98%. Niacin inhibited ... 

Inhibition by niacin of inflammatory and oxidative pathways may exert anti-atherosclerotic effects. In cultured human aortic endothelial cells, niacin increased cellular levels of nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) and glutathione, regulators of redox reactions, and reduced production of reactive oxygen species. Niacin inhibited monocyte adhesion through the inhibition of tumour necrosis factor-alpha (TNF-a) induced expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) (Ganji et al. 2009). Persistent increases in plasma adiponectin, an adipokine with anti-inflammatory properties, were found after 6 months of niacin treatment in humans (Linke et al. 2009). 

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