Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Measurement of the effect of drugs on the in vivo rates of synthesis of rabbit liver organelle bound proteins were measured following individual treatments with the inducers phenobarbital, 3-methylcholanthrene and PCB (a mixture of polychlorinated biphenyls) and the inhibitors, cycloheximide, aflatoxin B1, chloramphenicol and actinomycin D. Following their isolation from a homogenate containing the combined livers of 14C-leucine injected experimental animals and 3H-leucine injected control animals, purified fractions of the following proteins were prepared: microsomal cytochrome b5, cytochrome P-450, NADH-cytochrome b5 reductase, NADPH-cytochrome P-450 reductase and proteolipids, outer mitochondrial membrane cytochrome b5, NADH-cytochrome b5 reductase and proteolipids, inner mitochondrial membrane cytochrome c, NADH dehydrogenase and proteolipids, intermitochondrial membrane cytochrome b5 and circulating serum albumin. The effect of a drug was examined by measuring the 14C/3H ratio of leucine incorporation of each fraction; ratios which differed markedly from a control value of 1 represented actual changes in the relative rates of protein synthesis. Increased rates of synthesis of cytochrome P-450 and its reductase, intermitochondrial membrane cytochrome b5 and all three proteolipid fractions resulted from each inducer treatment. Treatments with 3-methylcholanthrene and PCB also increased the rate of synthesis of cytochrome b5 and its reductase in both the microsome and outer mitochondrial membrane. In addition, the PCB treatment increased the rates of synthesis of cytochrome c and NADH-dehydrogenase. The rates of synthesis of cytochromes, reductases and of circulating serum albumin were inhibited following treatments with cycloheximide, aflatoxin B1 and actinomycin D. Actinomycin D appeared to inhibit the release of newly synthesized albumin into the bloodstream while chloramphenicol treatment appeared to inhibit the incorporation of cytochrome c into the mitochondria. After 20 hours of treatment with inhibitors, the inhibitory effect of actinomycin D and cycloheximide were still apparent while the rates of protein synt;esis in chloramphenicol and aflatoxin B1 treated animals increased to levels above the controls. The incorporation of radioactively labeled leucine into the proteolipids of the microsomal, and the outer and inner mitochondrial membranes were inhibited following the treatment with actinomycin D and stimulated following the treatment with cycloheximide.
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PMID:Effect of a single dose of inducers and inhibitors on the rate of synthesis of cytochromes and reductases in liver organelles. 11 59

Previous studies with Adriamycin-sensitive and -resistant (ADRR) MCF-7 human breast tumor cell lines indicated that Adriamycin formed significantly less hydroxyl radical (.OH) as the result of enhanced detoxification of reactive oxygen intermediates in the ADRR cell line. In order to further define the sites of drug activation and the role of detoxification mechanisms in free radical levels, subcellular fractions were isolated from these two cell lines and free radical formation in the presence of Adriamycin was examined by using electron spin resonance spectroscopy. Studies reported here show that considerable NADPH-cytochrome P-450 reductase and NADH dehydrogenase activities were present in microsomes and mitochondria, respectively, and in nuclei obtained from these cells, and the relative activity of NADH dehydrogenase was 2-fold higher in the mitochondrial fraction of ADRR cells compared to the mitochondrial fraction from the parental wild type cells. In the presence of Adriamycin and a reducing cofactor (NADPH or NADH), Adriamycin semiquinone free radical, superoxide anion, and .OH were detected in all these fractions. Although only a small difference in the relative amount of oxy radical formation was detected in tumor microsomes, both mitochondria and nuclei of ADRR cells showed an overall 2-fold decreased formation of oxy radicals. The formation of the free radicals was significantly inhibited by superoxide dismutase, catalase, and dimethyl sulfoxide, indicating that free .OH generation was both superoxide and hydrogen peroxide dependent. The addition of purified glutathione peroxidase likewise inhibited .OH formation in a dose-dependent fashion. Similarly, when the lysate from ADRR cells, which contains 12- to 14-fold more glutathione peroxidase than Adriamycin-sensitive cells, was added to reaction mixtures containing Adriamycin-sensitive cells and Adriamycin, the .OH formation was diminished. Decreased free radical formation in nuclei and mitochondria, as a result of detoxification of hydrogen peroxide by glutathione peroxidase, may be significant in the protection of ADRR cells from Adriamycin-induced cell killing.
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PMID:Adriamycin activation and oxygen free radical formation in human breast tumor cells: protective role of glutathione peroxidase in adriamycin resistance. 254 60

5-(4-Nitrophenyl)penta-2,4-dienal (NPPD) stimulated NADPH-supported oxygen consumption by rat liver microsomes in a concentration-dependent manner. The NPPD stimulation of O2 uptake was not inhibited by metyrapone and was decreased in the presence of NADP+ and p-hydroxymercuribenzoate. These observations suggest that the NPPD initial reduction step is mediated by NADPH-cytochrome P-450 reductase and not by cytochrome P-450. Spin-trapping studies using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) revealed the formation of superoxide anion upon incubation of NPPD, NADPH, DMPO and rat liver microsomes. Hydrogen peroxide generation was also detected in these incubations, thus confirming redox cycling of NPPD under aerobic conditions. NPPD stimulated oxygen consumption, superoxide anion formation and hydrogen peroxide generation by rat kidney, testes and brain microsomes. Other enzymes capable of nitroreduction (NADH dehydrogenase, xanthine oxidase, glutathione reductase, and NADP+ ferredoxin oxidoreductase) were also found to stimulate redox cycling of NPPD. The ability of NPPD to induce superoxide anion and hydrogen peroxide formation might play a role in its reported mutagenicity.
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PMID:Generation of superoxide anion and hydrogen peroxide during redox cycling of 5-(4-nitrophenyl)-penta-2,4-dienal by mammalian microsomes and enzymes. 283 86

Results of comparative studies on stimulation of the rates of cofactor consumption, superoxide generation and hydrogen peroxide production by mitoxantrone (Novantrone; dihydroxyanthracenedione; MXN), ametantrone (AM), doxorubicin (DOX) and daunorubicin (DNR) in the presence of NADPH-cytochrome P-450 reductase, NADH dehydrogenase, or rabbit hepatic microsomes have been reported. MXN and AM were substantially less effective in stimulating the rate of cofactor oxidation, superoxide formation or hydrogen peroxide production relative to the anthracyclines. In the presence of P-450 reductase, the rate of NADPH oxidation or superoxide generation produced by 100 microM MXN or AM was only 15% and 2% respectively of that produced by 100 microM anthracycline. The effects of MXN and AM on lipid peroxidation in hepatic microsomes, cardiac sarcosomes and cardiac mitochondria were determined and compared with those produced by ADM. MXN and AM at 50 microM inhibited the basal rate of NADPH-dependent rabbit liver microsomal lipid peroxidation by 50%; in contrast, DOX enhanced the rate of hepatic microsomal lipid peroxidation by 2- and 2.5-fold at 100 and 200 microM, respectively. Rabbit cardiac sarcosomal NADPH-dependent lipid peroxidation was inhibited completely at 100 microM anthracenedione. NADH-dependent lipid peroxidation in cardiac mitochondria was diminished by 50 microM MXN and AM, whereas 50 microM DOX produced a 2-fold stimulation in lipid peroxidation. The anthracenediones also effectively inhibited DOX-stimulated lipid peroxidation with 50% inhibition occurring at 4 microM (MXN) and 6 microM (AM). Moreover, both MXN and AM potently inhibited iron (100 microM)-stimulated lipid peroxidation in rabbit hepatic microsomes with 80% inhibition produced by 15 microM anthracenedione.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitoxantrone: propensity for free radical formation and lipid peroxidation--implications for cardiotoxicity. 299 Nov 63

Stimulation of the rates of NAD(P)H oxidation, superoxide generation, and hydrogen peroxide formation by three anthracenedione antineoplastic agents in the presence of NADPH-cytochrome P-450 reductase, NADH dehydrogenase, or rabbit hepatic microsomes was studied and the results compared with those obtained for the anthracyclines Adriamycin and daunorubicin. In all cases the anthracenediones, including mitoxantrone and ametantrone, were significantly (5- to 20-fold) less effective than the anthracyclines in stimulating NAD(P)H oxidation, superoxide formation, or hydrogen peroxide production. Of the three anthracenediones studied, the ring-monohydroxylated compound showed the greatest activity followed by the ring-dihydroxylated derivative (mitoxantrone). In contrast, the non-ring-hydroxylated anthracenedione (ametantrone) was a relatively ineffective electron acceptor and inhibited the reduction of more effective acceptors such as Adriamycin. Michaelis-Menten kinetic constants were determined by analysis of the rates of NADPH oxidation. NADP+ and 2'-AMP inhibited the reduction of the ring-hydroxylated anthracenediones and anthracyclines, demonstrating the enzymatic nature of the reaction. The non-ring-hydroxylated anthracenedione inhibited the reduction of Adriamycin by both P-450 reductase and NADH dehydrogenase with 50% inhibition achieved at approximately 300 microM. Thus, there appears to exist a structural relationship between anthracenedione ring hydroxylation and metabolic activation. These results also suggest that the relative inability of the anthracenediones to function as artificial electron acceptors in comparison to the anthracyclines may be correlated with diminished anthracenedione cardiotoxicity.
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PMID:Bis(alkylamino)anthracenedione antineoplastic agent metabolic activation by NADPH-cytochrome P-450 reductase and NADH dehydrogenase: diminished activity relative to anthracyclines. 640 91

Adriamycin (or doxorubicin) is an active and broad spectrum chemotherapeutic agent. Unfortunately, its clinical use is severely restricted by a dose-limiting cardiotoxicity which has been linked to the formation of superoxide. Enzymatic one-electron reduction of adriamycin forms adriamycin semiquinone radical, which rapidly reacts with oxygen to form superoxide and adriamycin. In this way, adriamycin provides a kinetic mechanism for the one-electron reduction of oxygen by flavoenzymes such as NADPH-cytochrome P450 reductase and mitochondrial NADH dehydrogenase. We demonstrate here that the endothelial isoform of nitric oxide synthase (eNOS) reduces adriamycin to the semiquinone radical. As a consequence, superoxide formation is enhanced and nitric oxide production is decreased. Adriamycin binds to eNOS with a Km of approximately 5 microM, as calculated from both eNOS-dependent NADPH consumption and superoxide generation. Adriamycin stimulated superoxide formation is not affected by calcium/calmodulin and is abolished by the flavoenzyme inhibitor, diphenyleneiodonium. This strongly suggests that adriamycin undergoes reduction at the reductase domain of eNOS. A consequence of eNOS-mediated reductive activation of adriamycin is the disruption of the balance between nitric oxide and superoxide. This may lead eNOS to generate peroxynitrite and hydrogen peroxide, potent oxidants implicated in several vascular pathologies.
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PMID:Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. 933 25