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

A 'null' activity variant for the major liver isozyme of aldehyde oxidase (AOX-1) in adult male mice and an electrophoretically distinct, high activity variant of the second liver isozyme (AOX-2) were used to examine the segregation of the genetic loci encoding these enzymes (Aox-1 and Aox-2 respectively) in breeding studies. A single recombinant between these loci was observed among the 147 backcross progeny examined, which confirms a previous report (Holmes, 1979) for close linkage and genetic distinctness of the two loci. An activity variant for mouse liver xanthine oxidase (XOX) is also reported which behaved as though controlled by codominant alleles at a single locus (designated Xox-1). Genetic analyses showed that the Xox-1 locus segregated independently of the multiple-Aox loci.
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PMID:Liver aldehyde oxidase and xanthine oxidase genetics in the mouse. 689 82

The oxidation of O6-benzylguanine, an inactivator of O6-alkylguanine-DNA alkyltransferase, was examined using human liver cytosol, microsomes, and several P450 isoforms. Incubation of O6-benzylguanine with human liver cytosol resulted in the formation of O6-benzyl-8-oxoguanine, which was inhibited by menadione, a potent inhibitor of aldehyde oxidase. Inhibition by allopurinol, a xanthine oxidase inhibitor, was less dramatic. Oxidation of O6-benzylguanine also occurred with pooled human liver microsomes and was inhibited by both furafylline and troleandomycin, selective inhibitors of CYP1A2 and CYP3A4, respectively. Human P450s CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2E1, and CYP3A4 expressed in Hep G2 hepatoma cells using vaccinia virus vectors were incubated with 10 or 200 microM O6-benzylguanine. At 10 microM, O6-benzylguanine was oxidized primarily by CYP1A2 and to a lesser extent by CYP3A4. However, an appreciable increase in CYP3A4 contribution was noted at 200 microM. CYP1A2 exhibited a more than 200-fold higher relative catalytic activity (Vmax/Km) compared with CYP3A4. Therefore, at therapeutically relevant concentrations of O6-benzylguanine, CYP1A2 could be primarily involved in its oxidation since it shows a much lower Km value (1.3 microM) than CYP3A4 (52.2 microM) and cytosol (81.5 microM). However, one would expect interindividual variation in the extent of oxidation of O6-benzylguanine depending on the levels of aldehyde oxidase, CYP1A2, and CYP3A4.
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PMID:Human liver oxidative metabolism of O6-benzylguanine. 750 88

Liver cytosolic fractions are known to catalyze the reduction of certain C-nitroso compounds to their corresponding hydroxylamines and amines. Alcohol dehydrogenase (ADH), NAD(P)H:quinone oxidoreductase, and xanthine and aldehyde oxidases have been implicated as C-nitroso reductases. To probe the role of these cytosolic enzymes in the reduction of C-nitroso compounds we have studied the effects of classical inhibitors of these enzymes on the ability of liver cytosolic fractions from ADH+ and ADH- deermice to reduce p-nitrosophenol to p-aminophenol. Pyrazole, a potent inhibitor of ADH, inhibited NADH-p-nitrosophenol reduction by ADH+ cytosol by > 85%. Thus, ADH contributes substantially to NADH-C-nitroso reduction by cytosol from ADH+ deermice. The NAD(P)H:quinone oxidoreductase inhibitor, dicumarol, inhibited NADH-dependent p-aminophenol formation by about 25%; however, dicumarol potently inhibited the NADPH-dependent formation (90-95%). As expected, cytosol from ADH- deermice did not catalyze pyrazole-sensitive (ADH-dependent) C-nitroso reduction with NADH as the cofactor. Both NADPH- and NADH-p-nitrosophenol reduction by ADH- cytosol were inhibited > 90% by dicumarol. The xanthine oxidase/aldehyde oxidase inhibitor, allopurinol, was without effect on NAD(P)H cytosolic p-nitrosophenol reduction from ADH- and ADH+ deermice under either aerobic or anaerobic conditions. Our findings suggest that in the ADH+ animal, ADH contributes significantly to NADH-dependent C-nitroso reduction by cytosol relative to NAD(P)H:quinone oxidoreductase. NADPH-dependent p-nitrosophenol reduction by liver cytosol of ADH+ animals is mostly dicumarol-sensitive, which implicates NAD(P)H:quinone oxidoreductase as the major NADPH-dependent activity. In ADH- deermice, both NADH- and NADPH-dependent p-nitrosophenol reduction are essentially dicumarol-sensitive (NAD(P)H:quinone oxidoreductase-dependent). Because the toxic expression of C-nitroso compounds is mediated by hydroxylamine intermediates, the present data indicate the importance of considering the role of ADH in the toxic sequelae of nitro and nitroso arenes.
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PMID:p-nitrosophenol reduction by liver cytosol from ADH-positive and -negative deermice (Peromyscus maniculatus). 753 87

The properties of the molybdenum iron-sulfur flavoprotein, aldehyde oxidase from rabbit livers, have been further investigated in comparison with bovine milk xanthine oxidase. In agreement with earlier work, the ultraviolet/visible spectra indicate that the flavin and iron-sulfur centres of the enzymes are quite similar to one another. The molybdenum centres have been compared by EPR spectroscopy of molybdenum(V) and regarding re-insertion of the sulfido ligand of molybdenum into the desulfo enzyme forms. The pH optimum for sulfide insertion is approximately 2 lower for aldehyde oxidase than for xanthine oxidase. A detailed comparison of molybdenum(V) EPR signals has been made for the signals known as Arsenite, Slow and Rapid. Computer simulation of spectra in 1H2O and 2H2O, at 9 and 35 GHz was used. Slow signals from the two enzymes are scarcely distinguishable from one another. Under the conditions used, aldehyde oxidase yielded only the Rapid type 2 signal, whereas xanthine oxidase gives both the Rapid type 1 and 2 signals. The nature of the structural difference between the Rapid type 1 and type 2 signal-giving species is discussed. It is concluded that the molybdenum centres of xanthine oxidase and aldehyde oxidase are indeed similar to one another and that such differences as exist between their molybdenum(V) EPR signals and re-sulfuration properties are related to differences only in the substrate-binding sites. N-terminal amino acid analyses have been performed on peptides obtained by trypsin cleavage of aldehyde oxidase. Comparison with a sequence previously deduced [Wright, R. M., Vaitaitis, G. M., Wilson, C. M., Repine, T. B., Terada, L. S. & Repine, J. E. (1993) Proc. Natl Acad. Sci. USA 90, 10690-10694] makes it clear that the latter is not, as was assumed, that of a xanthine dehydrogenase but of an aldehyde oxidase. In contrast to the situation with xanthine oxidase, attempts to convert non-proteolysed aldehyde oxidase to a dehydrogenase form by treatment with dithiothreitol were unsuccessful. The reason for this is considered in the light of sequence data in the literature. The location of the NAD(+)-binding site is discussed, and the sequence data are also discussed in relation to the molybdenum, iron-sulfur and substrate-binding sites.
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PMID:Properties of rabbit liver aldehyde oxidase and the relationship of the enzyme to xanthine oxidase and dehydrogenase. 755 19

Famciclovir is the diacetyl 6-deoxy derivative of the active antiviral penciclovir that is for use in the treatment of infections caused by the herpes family of viruses. The major pathway of conversion is via di-deacetylation to BRL 42359, followed by oxidation to penciclovir. On oral dosing of famciclovir to humans, only penciclovir and BRL 42359 can be detected consistently in the plasma; thus, attention was focused on the oxidation reaction. This 6-oxidation occurred rapidly in human liver cytosol, had no requirement for cofactors, and followed simple Michaelis-Menten kinetics with a KM of 115 microM +/- 23 (N = 3). Using inhibitors of xanthine oxidase (allopurinol) and aldehyde oxidase (menadione and isovanillin), the relative roles of these enzymes in this process were determined. At a concentration of BRL 42359 that reflected plasma concentrations observed in humans (4 microM), both menadione (IC50 7 microM) and isovanillin (IC50 15 microM) caused extensive inhibition of the 6-oxidation reaction. In contrast, allopurinol caused no significant inhibition, confirming earlier in vivo work. At higher substrate concentrations (50 and 200 microM), the results with these inhibitors were broadly similar. These results provide strong evidence that aldehyde oxidase and not xanthine oxidase is responsible for the 6-oxidation of BRL 42359 to penciclovir in human liver cytosol, and this is likely to reflect the in vivo situation.
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PMID:Role of aldehyde oxidase in the in vitro conversion of famciclovir to penciclovir in human liver. 773 20

BRL 55792, BRL 55791, and BRL 55039 are prodrugs of an active antiviral agent 9-(3-hydroxypropoxy) guanine (BRL 44385). The prodrugs were 6-deoxygenated analogs of BRL 44385, with ether groups substituted at the 9-position: BRL 55792 with an (isopropoxymethyloxy)propoxy group, BRL 55791 with a (methoxymethyloxy)propoxy group, and BRL 55039 with an ethoxypropoxy group. Conversion of the prodrugs to BRL 44385 had been demonstrated in vivo in the rat and involved 6-oxidation followed by dealkylation. Metabolism was studied in rat liver in vitro systems to find a model to evaluate BRL 44385 production. Rat hepatocytes performed both reaction steps and were used to assess which of the three prodrugs demonstrated greatest production of the active drug. BRL 55792 demonstrated greatest conversion in vitro, and this was in agreement with in vivo data. The production of BRL 44385 from BRL 55792 was also demonstrated in human hepatocyte incubations, providing evidence that these reactions can occur in humans, thereby increasing confidence that BRL 55792 would be suitable prodrug for human therapy. Further experiments were performed to investigate the enzymes involved in these conversions. The 6-oxidation step occurred in the cytosol. Use of allopurinol and menadione (xanthine and aldehyde oxidase inhibitors) indicated that these conversions were catalyzed exclusively by xanthine oxidase in the rat but mainly by aldehyde oxidase in humans. The dealkylation reaction was detected in hepatocytes but not in homogenates or subcellular fractions. Inhibition of this reaction by aminobenzotriazole and ketoconazole (P-450 inhibitors) indicated that it was mediated by cytochrome P-450.
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PMID:Use of rat and human in vitro systems to assess the effectiveness and enzymology of deoxyguanine analogs as prodrugs of an antiviral agent. 801 73

In order to enhance the brain delivery of 2'-F-ara-ddI,2'-F-ara-ddP 6 was synthesized and its in vitro and in vivo bioconversion reaction studied. For the study, a new efficient synthetic method for 2'-F-ara-ddP 6 was developed from 5-benzoyl-1,2-O-isopropylidene-3-deoxyribose 1. For in vitro study 2'-F-ara-ddP was incubated in pH 2, mouse liver homogenate, and mouse serum at 37 degrees C. No degradation was observed in pH 2 and serum, while in liver homogenate 2'-F-ara-ddP was almost completely converted to 2'-F-ara-ddI within 20 min (t1/2 = 3.54 min). In order to determine the role of xanthine oxidase in the conversion of 2'-F-ara-ddP to 2'-F-ara-ddI, in vitro studies were conducted in phosphate buffer (pH 7.4) in the presence or absence of allopurinol, in which the half-lives of 2'-F-ara-ddP were 7.4 and 3.4 h, respectively, indicating the conversions were catalyzed by the xanthine oxidase. A similar experiment with aldehyde oxidase isolated from the human liver did not affect the biotransformation. The biotransformation was also detected in the brain homogenate, although the rate of conversion was low and incomplete. In order to assess the bioconversion in vivo, pharmacokinetic studies of 2'-F-ara-ddP and 2'-F-ara-ddI were conducted in mice. The maximum serum concentrations of 2'-F-ara-ddI administered itself and as 2'-F-ara-ddP reached 48.1 +/- 10.00 and 89.3 +/- 26.0 microM and were observed in 1 and 0.25 h, respectively. The data indicate that 2'-F-ara-ddI is absorbed at a slower rate than that of 2'-F-raa-ddP. The bioavailability of the prodrug after oral administration was 60.7%. The concentration of 2'-F-ara-ddI following oral administration of 2'-ara-ddI was close to the detection limits while 2'-F-ara-ddI was detected at significantly higher concentrations in the brain after oral administration of 2'-F-ara-ddP. From this study, we have administered the enhanced brain delivery of anti-HIV nucleoside utilizing an in vivo biotransformation system.
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PMID:Enhanced brain delivery of an anti-HIV nucleoside 2'-F-ara-ddI by xanthine oxidase mediated biotransformation. 814 33

BRL 55792, BRL 55791, and BRL 55039 are prodrugs of an active anti-viral agent 9-(3-hydroxypropoxy) guanine, (BRL 44385). The prodrugs were 6-deoxygenated analogues of BRL 44385 with ether groups substituted at the 9-position: BRL 55792 with an (isopropoxymethyloxy)propoxy group, BRL 55791 with a (methoxymethyloxy)propoxy group, and BRL 55039 with an ethoxypropoxy group. Conversion of the prodrugs to BRL 44385 had been demonstrated in vivo in rat and involved 6-oxidation followed by dealkylation. Metabolism was studied in rat liver in vitro systems to find a model to evaluate BRL 44385 production. Rat hepatocytes performed both reaction steps and were used to assess which of the three prodrugs demonstrated greatest production of the active drug. BRL 55792 demonstrated greatest conversion in vitro and this was in agreement with in vivo data. The production of BRL 44385 from BRL 55792 was also demonstrated in human hepatocyte incubations providing evidence that these reactions can occur in man thereby increasing confidence that BRL 55792 would be a suitable prodrug for human therapy. Further experiments were performed to investigate the enzymes involved in these conversions. The 6-oxidation step occurred in the cytosol. Use of allopurinol and menadione (xanthine and aldehyde oxidase inhibitors) indicated that these conversions were catalyzed exclusively by xanthine oxidase in the rat but mainly by aldehyde oxidase in man. The dealkylation reaction was detected in hepatocytes but not in homogenates or subcellular fractions. Inhibition of this reaction by aminobenzotriazole and ketoconazole (P-450 inhibitors) indicated that it was mediated by cytochrome P-450.
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PMID:Use of rat and human in vitro systems to assess the effectiveness and enzymology of deoxy-guanine analogues as prodrugs of an antiviral agent. 814 71

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

Aldehyde oxidase was purified about 120-fold from rat liver cytosol by sequential column chromatography using diethylaminoethyl (DEAE) cellulose, Benzamidine-Sepharose 6B and gel filtration. The purified enzyme was shown as a single band with M(r) of 2.7 x 10(5) on polyacrylamide gel electrophoresis (PAGE) and M(r) of 1.35 x 10(5) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Using this purified enzyme, in vitro conversion of allopurinol, pyrazinamide and pyrazinoic acid was investigated. Allopurinol and pyrazinamide were oxidized to oxypurinol and 5-hydroxy-pyrazinamide, respectively, while pyrazinoic acid, the microsomal deamidation product of pyrazinamide, was not oxidized to 5-hydroxypyrazinoic acid. The apparent Km value of the enzyme for pyrazinamide was 160 microM and that for allopurinol was 1.1 mM. On PAGE, allopurinol- or pyrazinamide-stained band was coincident with Coomassie Brilliant Blue R 250-stained band, respectively. These results suggest that aldehyde oxidase may play a role in the oxidation of allopurinol to oxypurinol and that of pyrazinamide to 5-hydroxypyrazinamide with xanthine dehydrogenase which can oxidize both allopurinol and pyrazinamide in vivo. The aldehyde oxidase may also play a major role in the oxidation of allopurinol and pyrazinamide in the subgroup of xanthinuria patients (xanthine oxidase deficiency) who can oxidize both allopurinol and pyrazinamide.
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PMID:In vitro oxidation of pyrazinamide and allopurinol by rat liver aldehyde oxidase. 821 57


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