Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We reported previously that p.o. administered 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was efficiently converted to 5-iodo-2'-deoxyuridine (IUdR) in athymic mice (T. J. Kinsella et al., Cancer Res., 54: 2695-2700, 1994). Here, we further evaluate IPdR metabolism, systemic toxicity, and percentage DNA incorporation in athymic mouse normal tissues and a human colon cancer xenograft (HT29) using higher p.o. doses of IPdR. These data are compared to results using a continuous infusion of IUdR at the maximum tolerable dose. We also evaluate IPdR metabolism in cytosolic extracts from normal human liver, normal human intestine, and human colorectal cancer specimens. Athymic mice tolerated a daily p.o. bolus of up to 2 g/kg IPdR for 6 days with minimal host toxicity (< or = 10% body weight loss). There was rapid conversion of IPdR to IUdR, with peak plasma levels of IUdR of 40-75 microM at 10 min following a p.o. IPdR bolus of 250-1500 mg/kg. The percentage IUdR-DNA in the HT29 s.c. human tumor xenografts increased 1.5 times (2.3-3.6%) with IPdR doses above 1 g/kg/day for 6 days, whereas the percentage IUdR-DNA incorporation in two proliferating normal tissues (4-4.5% in intestine; 1.6-2.2% in bone marrow) and a quiescent normal tissue (< or = 1% in liver) showed < 1.5-fold increases with the IPdR dose escalation between 1-2 g/kg/day for 6 days. In contrast, using a continuous infusion of IUdR at 100 mg/kg/day, significant systemic toxicity (> 20% body weight loss) was found by day 6 of the infusion. Steady-state plasma IUdR levels were 1.0-1.2 microM during the 6-day infusion, and percentage IUdR-DNA incorporations of 2.3, 8, 6, and 1% were measured in s.c. tumors, normal intestine, normal bone marrow, and normal liver, respectively, following the 6-day infusion. Thus, the p.o. IPdR schedule has an improved therapeutic index, based on percentage IUdR-DNA incorporation in normal and tumor tissues, compared to continuous infusion IUdR at the maximum tolerable dose in athymic mice with this human tumor xenograft. Additionally, a tumor regrowth assay to assess the radiation response of HT29 s.c. xenografts showed a 1.5-fold enhancement (time to regrow to 300% initial tumor volume) with IPdR (1000 mg/kg/day for 6 days) plus fractionated irradiation (XRT; 2 Gy/day for 4 days), compared to XRT (2 Gy/day for 4 days) alone. No enhancement in the radiation response of HT29 s.c. xenografts was found with continuous infusion IUdR (100 mg/kg/day for 6 days) plus XRT (2 Gy/day for 4 days), compared to XRT alone. Using cytosolic extracts from normal human liver specimens, we found a rapid (15-min) conversion of IPdR to IUdR. Coincubation of liver cytosol with IPdR and allopurinol, an inhibitor of xanthine oxidase, had no inhibitory effect on IPdR metabolism, whereas coincubation with IPdR and isovanillin or menadione, analogue substrates for aldehyde oxidase, effectively reduced the amount of IPdR oxidized to IUdR. Significantly less metabolism of IPdR to IUdR was seen in cytosolic extracts from normal human intestine specimens, and no metabolism of IPdR was found in cytosolic extracts from colorectal liver metastases in two patients and from the HT29 human colon cancer xenografts in athymic mice. These additional data indicate that IPdR has the potential for clinical use as a p.o. prodrug for IUdR-mediated radiosensitization of resistant human cancers.
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PMID:Preclinical evaluation of 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine-mediated radiosensitization in mouse and human tissues. 951 58

We describe an enzymatic histochemical localization of two allopurinol-oxidizing enzymes, xanthine oxidase and aldehyde oxidase in rat hepatic tissues. This method is based on the tetrazolium salt procedures by use of a tissue protectant, polyvinyl alcohol, with tetra-nitro BT as the final electron acceptor. The present study demonstrated that both oxidases are present in the cytoplasm of hepatic cells. However, the distribution of the enzymes was uneven, being seen mainly in the pericentral rather than the periportal area. When allopurinol was used as a substrate, the specific staining by xanthine oxidase was more prominent than that of aldehyde oxidase. The results suggested that xanthine oxidase is more effective in oxidizing allopurinol than aldehyde oxidase.
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PMID:Zonal distribution of allopurinol-oxidizing enzymes in rat liver. 959 29

Aldehyde oxidases and xanthine dehydrogenases/oxidases belong to the molybdenum cofactor dependent hydroxylase class of enzymes. Zymograms show that Arabidopsis thaliana has at least three different aldehyde oxidases and one xanthine oxidase. Three different cDNA clones encoding putative aldehyde oxidases (AtAO1, 2, 3) were isolated. An aldehyde oxidase is the last step in abscisic acid (ABA) biosynthesis. AtAO1 is mainly expressed in seeds and roots which might reflect that it is involved in ABA biosynthesis.
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PMID:Biochemical and genetic characterization of three molybdenum cofactor hydroxylases in Arabidopsis thaliana. 965 45

Methotrexate (MTX) was investigated for possible effect on the metabolism of ethoxyresorufin, pentoxyresorufin and ethoxycoumarin, the model substrates of cytochrome P450. The investigation was carried out in liver microsomes of rats pretreated with classical inducers of cytochrome P450 as well as in microsomes of two human livers. Furthermore, we measured the conversion of MTX (100microM) to its main metabolite, 7-hydroxymethotrexate (7-OHMTX), in microsomes and cytosolic fractions of rat and human livers. The inhibition of 7-OHMTX formation by menadion (inhibitor of aldehyde oxidase) and allopurinol (inhibitor of xanthine oxidase) was studied in the cytosol of rat and human livers. In both species, MTX in the concentration range 0.5-500 microM exerted no inhibitory effect on enzymatic activities associated with cytochrome P450. Moreover, we did not observe any measurable formation of 7-OHMTX in liver microsomes. MTX was metabolized at a similar rate in the cytosol of rat and human liver. Allopurinol (100 microM) reduced the rate of MTX hydroxylation by 31.5% in the cytosol of human livers but had no effect in the rat. Menadion (100 microM) decreased the rate of 7-OHMTX formation in the cytosol of human and rat liver by 69% and 94%, respectively. Our results confirmed that MTX is oxidized by a soluble enzymatic system in both the rat and human liver. In human tissues, both aldehyde oxidase and xanthine oxidase may play an important role in the metabolism of MTX. Depression of cytochrome P450 and related enzymatic activities observed in vivo cannot be explained by a direct inhibitory action of MTX on cytochrome P450.
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PMID:An in vitro study on methotrexate hydroxylation in rat and human liver. 972 83

Alcohol consumption increases the risk for breast cancer in women by still undefined means. Alcohol metabolism is known to produce reactive oxygen species (ROS), and breast cancer is associated with high levels of hydroxyl radical (*OH) modified DNA, point mutations, single strand nicks, and chromosome rearrangement. Furthermore, ROS modification of DNA can produce the mutations and DNA damage found in breast cancer. Alcohol dehydrogenase (ADH) and xanthine oxidoreductase (XOR) are expressed and regulated in breast tissues and aldehyde oxidase (AOX) may be present as well. Mammary gland XOR is an efficient source of ROS. Recently, hepatic XOR and AOX were found to generate ROS in two ways from alcohol metabolism: by acetaldehyde consumption and by the intrinsic NADH oxidase activity of both XOR and AOX. The data obtained suggests that: (1) expression of ADH and XOR or AOX in breast tissue provides the enzymes that generate ROS; (2) metabolism of alcohol produces acetaldehyde and NADH that can both be substrates for XOR or AOX and thereby result in ROS formation; and (3) ROS generated by XOR or AOX can induce the carcinogenic mutations and DNA damage found in breast cancer. Accumulation of iron coupled with diminished antioxidant defenses in breast tissue with advancing age provide additional support for this hypothesis because both result in elevated ROS damage that may exacerbate the risk for ROS-induced breast cancer.
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PMID:Alcohol-induced breast cancer: a proposed mechanism. 989 26

The kinetics of xanthine oxidase has been investigated with the aim of addressing several outstanding questions concerning the reaction mechanism of the enzyme. Steady-state and rapid kinetic studies with the substrate 2,5-dihydroxybenzaldehyde demonstrated that (kcat/Km)app and kred/Kd exhibit comparable bell-shaped pH dependence with pKa values of 6.4 +/- 0.2 and 8.4 +/- 0.2, with the lower pKa assigned to an active-site residue of xanthine oxidase (possibly Glu-1261, by analogy to Glu-869 in the crystallographically known aldehyde oxidase from Desulfovibrio gigas) and the higher pKa to substrate. Early steps in the catalytic sequence have been investigated by following the reaction of the oxidized enzyme with a second aldehyde substrate, 2-aminopteridine-6-aldehyde. The absence of a well defined acid limb in this pH profile and other data indicate that this complex represents an Eox.S rather than Ered.P complex (i.e. no chemistry requiring the active-site base has taken place in forming the long wavelength-absorbing complex seen with this substrate). It appears that xanthine oxidase (and by inference, the closely related aldehyde oxidases) hydroxylates both aromatic heterocycles and aldehydes by a mechanism involving base-assisted catalysis. Single-turnover experiments following incorporation of 17O into the molybdenum center of the enzyme demonstrated that a single oxygen atom is incorporated at a site that gives rise to strong hyperfine coupling to the unpaired electron spin of the metal in the MoV oxidation state. By analogy to the hyperfine interactions seen in a homologous series of molybdenum model compounds, we conclude that this strongly coupled, catalytically labile site represents a metal-coordinated hydroxide rather than the Mo=O group and that this Mo-OH represents the oxygen that is incorporated into product in the course of catalysis.
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PMID:The reductive half-reaction of xanthine oxidase. Reaction with aldehyde substrates and identification of the catalytically labile oxygen. 992 Aug 73

The distribution of aldehyde oxidase activity was evaluated in unfixed cryostat sections from tissues of male Wistar rats using a tissue protectant, polyvinyl alcohol, with Tetranitro BT as a final electron acceptor. The distribution of aldehyde oxidase activity was compared with that of xanthine oxidoreductase. The enzyme histochemical method demonstrated aldehyde oxidase activity in the epithelium of the tongue, renal tubules and bronchioles, as well as in the cytoplasm of liver cells. Such activity was not detected in oesophagus, stomach, spleen, adrenal glands, small or large intestine or skeletal and heart muscle fibres. In contrast, xanthine oxidoreductase activity was demonstrated in the tongue, renal tubules, bronchioles, oesophageal, gastric, small and large intestinal epithelial cells, adrenal glands, spleen and liver cytoplasm but not in skeletal and heart muscle fibres. The significance of the ubiquitous distribution of aldehyde oxidase activity, especially in surface epithelial cells from various tissues, except for the gastrointestinal tract, is unclear. However, aldehyde oxidase may possess some physiological activity other than in the metabolism of N-heterocyclics or of certain drugs.
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PMID:Comparative localization of aldehyde oxidase and xanthine oxidoreductase activity in rat tissues. 1019 46

The role of sex hormones in hepatic lipid peroxidation, and in hepatic aldehyde oxidase and xanthine oxidase activities were investigated using rat liver homogenates. It was observed that male rat had a significantly greater content of malondialdehyde in liver than female. Among the sex hormones tested, estradiol, one of female hormones, markedly inhibited the formation of lipid peroxides in liver tissues in vitro. Especially, the inhibitory effect of estradiol appeared more remarkably in Fe+2-induced lipid peroxidation. The hepatic xanthine oxidase activity was decreased about 15% by 10(-6) M estradiol, whereas, the aldehyde oxidase activity was almost completely disappeared at the same concentration of estradiol. It implies that sex differences in lipid peroxidation is attributed to the suppression of free radical generating system by estradiol.
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PMID:Effect of sex hormones on lipid peroxidation in rat liver. 1031 41

Converting activity of methotrexate (MTX) to 7-hydroxymethotrexate (7-OH-MTX) was examined using eight strains of rats. Marked variability of the activity was found in liver cytosols from the rats. The highest activity was observed with Sea:SD rats, followed by LEW/Sea and Jcl:Wistar rats. The lowest activity was observed with WKA/Sea rats. The difference in the activity between Sea:SD and WKA/Sea strains was 104-fold. The variation was correlated to the strain difference of benzaldehyde oxidase activity in the rats. The cytosolic 7-hydroxylase activities in other tissues of Sea:SD rats were much higher than those of WKA/Sea, similarly to the case in liver. The liver microsomes of Sea:SD rats exhibited no 7-hydroxylase activity toward MTX even in the presence of NADPH. The cytosolic 7-hydroxylating activity of the livers of Sea:SD rats was inhibited by menadione, beta-estradiol, chlorpromazine and disulfiram, inhibitors of aldehyde oxidase, but not oxypurinol, an inhibitor of xanthine oxidase. The purified aldehyde oxidase from the livers of Sea:SD rats exhibited a significant 7-hydroxylating activity toward MTX. However, xanthine oxidase had no ability to hydroxylate MTX. These facts suggest that MTX hydroxylating activity in rats is predominantly due to aldehyde oxidase, and the strain differences are due to the variations of the flavoenzyme level.
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PMID:Strain differences of the ability to hydroxylate methotrexate in rats. 1033 93

Although 7-hydroxymethotrexate is a major metabolite of methotrexate during high-dose therapy, negligible methotrexate-oxidizing activity has been found in-vitro in the liver in man. The goals of this study were to determine the role of aldehyde oxidase in the metabolism of methotrexate to 7-hydroxymethotrexate in the liver and to study the effects of inhibitors and other substrates on the metabolism of methotrexate. Methotrexate, (+/-)-methotrexate and (-)-methotrexate were incubated with partially purified aldehyde oxidase from the liver of rabbit, guinea-pig and man and the products analysed by HPLC. Rabbit liver aldehyde oxidase was used for purposes of comparison. In-vitro aldehyde oxidase from the liver of man catalyses the oxidation of methotrexate to 7-hydroxymethotrexate, but the turnover is low. However, formation of 7-hydroxy-methotrexate from all forms of methotrexate by the liver in guinea-pig and man was significantly inhibited in the presence of 100 microM menadione and chlorpromazine, potent inhibitors of aldehyde oxidase. Allopurinol (100 microM) had a negligible inhibitory effect on liver aldehyde oxidase from guinea-pig and man. Allopurinol is a xanthine oxidase inhibitor. The production of 7-hydroxymethotrexate was enhanced in the presence of allopurinol. Although aldehyde oxidase is also responsible for some of this conversion, it is also possible that the closely related xanthine oxidase is responsible for the formation of 7-hydroxymethotrexate. By employing potent selective inhibitors of aldehyde oxidase, menadione and chlorpromazine, we have demonstrated for the first time that liver aldehyde oxidase from man is minimally involved in methotrexate oxidation.
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PMID:Aldehyde oxidase-catalysed oxidation of methotrexate in the liver of guinea-pig, rabbit and man. 1038 13


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