Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.99.3 (diaphorase)
 5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Compound LY56110 was well absorbed but slowly excreted in the rat, dog, and monkey. Oral administration of 5 mg/kg of [14C]LY56110 (5-bis(4-chlorophenyl)methylpyrimidine) to the rat, monkey, and dog resulted in a total excretion of 68, 65, and 30% of the radioactivity within 5 days, respectively. Very low urinary excretion was observed in the rat and dog (2%), with fecal excretion being the predominant mode of elimination in all three species. The plasma radioactivity half-life was 49, 41, and greater than 100 hr in the rat, monkey, and dog, respectively. The plasma half-life of parent compound was 18 hr in the rat and 10 hr in the dog. LY56110 accounted for only 25, 12, and 1% of the plasma radioactivity area under the curve in the rat, dog, and monkey, respectively. High levels of radioactivity were observed in the target tissues of fat, adrenals, and ovaries of rats. LY56110 induced hepatic cytochromes b5 and P-450 and cytochrome c reductase in rats after 14 days of oral dosing at 10 mg/kg but not in monkeys after 10 days of oral dosing at 10 mg/kg. The compound was more potent than aminoglutethimide or cimetidine in inhibiting hepatic ethylmorphine and p-nitroanisole demethylase activity in vitro. LY56110 also inhibited ethinamate-induced sleeping time in rats in vivo. The compound induced a reverse type I binding spectrum with rat ovarian microsomes.
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PMID:Disposition of the aromatase inhibitor LY56110 and associated induction and inhibition studies in rats, dogs, and monkeys. 360 45

Mitochondrial protein tyrosine phosphorylation is an important mechanism for the modulation of mitochondrial functions. In the present study, we have identified novel substrates of c-Src in mitochondria and investigated their function in the regulation of oxidative phosphorylation. The Src family kinase inhibitor PP2 {amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4d] pyrimidine} exhibits significant reduction of respiration. Similar results were obtained from cells expressing kinase-dead c-Src, which harbours a mitochondrial-targeting sequence. Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants. Comparison of cells expressing wild-type proteins and their mutants reveals that NDUFV2 phosphorylation is required for NADH dehydrogenase activity, affecting respiration activity and cellular ATP content. SDHA phosphorylation shows no effect on enzyme activity, but perturbed electron transfer, which induces reactive oxygen species. Loss of viability is observed in T98G cells and the primary neurons expressing these mutants. These results suggest that mitochondrial c-Src regulates the oxidative phosphorylation system by phosphorylating respiratory components and that c-Src activity is essential for cell viability.
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PMID:Mitochondrial c-Src regulates cell survival through phosphorylation of respiratory chain components. 2282 20