Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Ethynyluracil is a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) in vitro (Porter et al., J Biol Chem 267: 5236-5242, 1992) and in vivo (Spector et al., Biochem Pharmacol, 46: 2243-2248, 1993. 5-Ethynyl-2(1H)-pyrimidinone was rapidly oxidized to 5-ethynyluracil by aldehyde oxidase. The substrate efficiency (kcat/Km) was 60-fold greater than that for N-methylnicotinamide. In contrast, xanthine oxidase oxidized 5-ethynyl-2(1H)-pyrimidinone to 5-ethynyluracil with a substrate efficiency that was only 0.02% that of xanthine. Because 5-ethynyl-2(1H)-pyrimidinone did not itself inactivate purified DPD in vitro and aldehyde oxidase is predominately found in liver, we hypothesized that 5-ethynyl-2(1H)-pyrimidinone could be a liver-specific inactivator of DPD. We found that 5-ethynyl-2(1H)-pyrimidinone administered orally to rats at 2 micrograms/kg inactivated DPD in all tissues studied. Although 5-ethynyl-2(1H)-pyrimidinone produced slightly less inactivation than 5-ethynyluracil, the two compounds showed fairly similar patterns of inactivation of DPD in these tissues. At doses of 20 micrograms/kg, however, 5-ethynyl-2-pyrimidinone and 5-ethynyluracil produced equivalent inactivation of DPD. Thus, 5-ethynyl-2(1H)-pyrimidinone appeared to be an efficient, but not highly liver-selective prodrug of 5-ethynyluracil.
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PMID:5-ethynyl-2(1H)-pyrimidinone: aldehyde oxidase-activation to 5-ethynyluracil, a mechanism-based inactivator of dihydropyrimidine dehydrogenase. 816 45

This study investigated the effect of protein malnutrition on metabolism and toxicity of cisplatin (CP), 5-fluorouracil (FU) and mitomycin C (MMC) in rat stomach. Weanling male Wistar rats received a normal (24%) or low (2.5%) protein diet for 28 days and were allocated into: normally-fed control, protein-malnourished control (PM), 3 normally-fed drug-treated groups and 3 protein-malnourished drug-treated groups (PM-CP, PM-FU and PM-MMC). Cisplatin and MMC were injected intraperitoneally (8 mg/kg on day 26 and 1 mg/kg/day for 7 days, respectively). 5-Fluorouracil was given orally (50 mg/kg/day for 5 days). Compared with normally-fed counterparts, PM-CP rats exhibited higher glutathione S-transferase, aminopeptidase N and cysteine S-conjugate beta-lyase (CCBL) and lower gamma-glutamyltransferase activities, PM-FU rats exhibited decreased dihydropyrimidine dehydrogenase and cytochrome P450 1A1/2 activities and PM-MMC rats showed higher quinone reductase and depleted xanthine oxidase activities. Protein-malnourished drug-treated groups exhibited exacerbated gastrotoxicity, relative to normally-fed counterparts, manifested by lower mucus levels, higher permeability and histopathological deterioration, along with increased oxidative stress in PM-CP rats and exaggerated prostaglandin E2 production in PM-MMC rats. Conclusively, protein malnutrition alters CP, FU and MMC metabolism in rat stomach by enhancing CCBL pathway for CP activation, delaying FU elimination and activating two-electron reduction of MMC, potentiating their gastrotoxicity.
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PMID:Effect of protein malnutrition on the metabolism and toxicity of cisplatin, 5-fluorouracil and mitomycin C in rat stomach. 2345 48

Adenocarcinoma, a type of non-small cell lung cancer, is the most frequently diagnosed lung cancer and the leading cause of lung cancer mortality in the United States. It is well documented that biochemical changes occur early in the transition from normal to cancer cells, but the extent to which these alterations affect tumorigenesis in adenocarcinoma remains largely unknown. Herein, we describe the application of mass spectrometry and multivariate statistical analysis in one of the largest biomarker research studies to date aimed at distinguishing metabolic differences between malignant and nonmalignant lung tissue. Gas chromatography time-of-flight mass spectrometry was used to measure 462 metabolites in 39 malignant and nonmalignant lung tissue pairs from current or former smokers with early stage (stage IA-IB) adenocarcinoma. Statistical mixed effects models, orthogonal partial least squares discriminant analysis and network integration, were used to identify key cancer-associated metabolic perturbations in adenocarcinoma compared with nonmalignant tissue. Cancer-associated biochemical alterations were characterized by (i) decreased glucose levels, consistent with the Warburg effect, (ii) changes in cellular redox status highlighted by elevations in cysteine and antioxidants, alpha- and gamma-tocopherol, (iii) elevations in nucleotide metabolites 5,6-dihydrouracil and xanthine suggestive of increased dihydropyrimidine dehydrogenase and xanthine oxidoreductase activity, (iv) increased 5'-deoxy-5'-methylthioadenosine levels indicative of reduced purine salvage and increased de novo purine synthesis, and (v) coordinated elevations in glutamate and UDP-N-acetylglucosamine suggesting increased protein glycosylation. The present study revealed distinct metabolic perturbations associated with early stage lung adenocarcinoma, which may provide candidate molecular targets for personalizing therapeutic interventions and treatment efficacy monitoring.
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PMID:Metabolomic markers of altered nucleotide metabolism in early stage adenocarcinoma. 2565 18