Xanthine oxidase type D (dehydrogenase) in the intestine and other organs of the rat

Battelli, Maria Giulia; Corte, E. Della; Stirpe, Fiorenzo

doi:10.1042/bj1260747

Cited by 188 publications

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“…The intestine, especially the upper GI tract, is known to be rich in xanthine oxidase [37], an enzyme considered to be a major source of oxygen radicals during reperfusion [38] and during other forms of mucosal injury [39], and which is a classically known source ofsuperoxide radicals [40]. In particular, xanthine oxidase may be preferentially activated in bouts of ulcerative colitis (from the non-oxidant-producing dehydrogenase form to the oxidant-producing oxidase form) either by proteases released either from inflammatory cells or by lysosomal proteases released during epithelial cell death.…”

Section: Sources Of Mucosal Superoxide In Ulcerative Colitismentioning

confidence: 99%

Oxygen radicals in ulcerative colitis

Babbs

1992

Free Radical Biology and Medicine

270

169

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This article reviews the pathophysiologic concept that superoxide and hydrogen peroxide, generated by activated leukocytes, together with low-molecular-weight chelate iron derived from fecal sources and from denatured hemoglobin, amplify the inflammatory response and subsequent mucosal damage in patients with active episodes of ulcerative colitis. The putative pathogenic mechanisms reviewed are as follows: ( l ) Dietary iron is concentrated in fecal material owing to normally limited iron absorption. (2) Mucosal bleeding, characteristic of ulcerative colitis, as well as supplemental oral iron therapy for chronic anemia, further conspire to maintain or elevate mucosal iron concentration in colitis. (3) Fenton chemistry, driven especially by leukocyte-generated superoxide and hydrogen peroxide, leads to formation of hydroxyl radicals. (4) The resultant oxidative stress leads to the extension and propagation of crypt abscesses, either through direct membrane disruption by lipid peroxidation or through generation of secondary toxic oxidants such as chloramines. (5) Chemotactic products of lipid peroxidation, including 4-hydroxynonenal, provide positive feedback to accelerate this inflammatory/oxidative process, leading to acute exacerbations of the disease. (6) Other oxidized products, such as oxidized tryptophan metabolites, created by free radical mechanisms in or near the mucosa, may act as carcinogens or tumor promotors that contribute to the exceedingly high incidence of colon carcinoma in patients suffering from chronic ulcerative colitis. In this way, self-sustaining cycles of oxidant formation may amplify flare-ups of inflammation and mucosal injury in ulcerative colitis. This concept, if proved correct by subsequent research, would provide a rationale for several novel clinical approaches to the management of ulcerative colitis, including use of SOD mimetics, iron chelators, and chain-breaking antioxidants.

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Section: Sources Of Mucosal Superoxide In Ulcerative Colitismentioning

confidence: 99%

Oxygen radicals in ulcerative colitis

Babbs

1992

Free Radical Biology and Medicine

270

169

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“…During the isolation of xanthine oxidase from the kidney, addition of thiols such as ~-mercaptoethanol or dithiothreitol were omitted in the homogenization buffer but the enzyme preparations were preincubated in the presence of 10 mM DTT at 37°C for 30 min [2] in order to transform the reversible form of type-O xanthine oxidase into the D-type enzyme. To remove the renal endogenous substrates from the enzyme preparations, dialysis [13] instead of Sephadex G-25 column [6][7][8]10] was carried out because in our hands the latter procedure gave higher basal levels.…”

Section: Resultsmentioning

confidence: 99%

“…The supernatant was dialyzed for at least five hours against the same buffer [13] at 4°C. The enzyme preparations (0.25 ml = 40 mg tissue) were preincubated for 30 rain at 37°C in the presence of 10 mM DTT [2]. The assay of both XDH and total xanthine oxidase (XO + XDH) activity was carried out as reported [11] with some modifications.…”

Section: Animalsmentioning

confidence: 99%

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Lack of conversion of xanthine dehydrogenase to xanthine oxidase during warm renal ischemia

1990

FEBS Letters

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Irreversible transformation of xanthine dehydrogenase (XDH) to xanthine oxidase (XO) during ischemia was determined measuring XDH and total enzyme activity in kidneys before and after 60 min of clamp of the renal pedicle. Tissue levels of adenine nucleotides, xanthine and hypoxanthine were used as indicators of ischemia. After 60 min of clamping, ATP levels decreased by 72% with respect to controls whereas xanthine and hypoxanthine progressively reached tissue concentrations of 732+49 and 979+ 15 nmol-g tissue -1, respectively. Both total and XDH activities in ischemic kidneys (30 + 15 and 19 + 1 nmol'min-l'g tissue-I) were significantly lower than in controls when expressed on a tissue weight basis. The fraction of enzyme in the XDH form was however unchanged indicating that the reduction of the nucleotide pool is not accompanied by induction of the type-O activity of xanthine oxidase.

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“…Xanthine oxidase activity was based upon that reported by DellaCorte for the rat (80 mUnits/g). 40 Our initial computational models, variations of which were also studied, contained 50 mM polyunsaturated fatty acids susceptible to lipid peroxidation, and 1 mM hypoxanthine, and 0.15 M xanthine oxidase. This amount of hypoxanthine was sufficient to metabolize 1 mM hypoxanthine to uric acid in about 15 min.…”

Section: Initial Conditionsmentioning

confidence: 99%

Simulation of free radical reactions in biology and medicine: A new two-compartment kinetic model of intracellular lipid peroxidation☆

Babbs

Steiner

1990

Free Radical Biology and Medicine

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--To explore mechanisms of free radical reactions leading to intracellular lipid peroxidation in living systems, we developed a computational model of up to 109 simultaneous enzymatic and free radical reactions thought to be involved in the initiation, propagation, and termination of membrane lipid peroxidation. Rate constants for the various reactions were obtained from the published literature. The simulation model included a lipid membrane compartment and an aqueous cytosolic compartment, between which various chemical species were partitioned. Lipid peroxidation was initiated by the iron-catalyzed, superoxide-driven Fenton reaction. A "C"-language computer program implemented numerical solution of the steady-state rate equations for concentrations of nine relevant free radicals. The rate equations were integrated by a modified Euler technique to describe the evolution with time of simulated concentrations of hydrogen peroxide, ferric and ferrous iron, unsaturated lipid, lipid hydroperoxides, superoxide anion, and biological antioxidants, including SOD and catalase. Initial results led to significant insights regarding mechanisms of membrane lipid peroxidation:1.segregation and concentration of lipids within membrane compartments promotes chain propagation; 2.in the absence of antioxidants computed concentrations of lipid hydroperoxides increase linearly about 40 M/min during oxidative stress; 3.lipid peroxidation is critically dependent upon oxygen concentration and the modeled dependence is similar to the experimental function; 4.lipid peroxidation is rapidly quenched by the presence of Vitamin E-like antioxidants, SOD, and catalase; 5.only small (l to 50 M) amounts of "free" iron are required for initiation of lipid peroxidation; 6. substantial lipid peroxidation occurs only when cellular defense mechanisms have been weakened or overcome by prolonged oxidative stress, hence understanding of the balance between free radical generation and antioxidant defense systems is critical to the understanding and control of free radical reactions in biology and medicine.

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Xanthine oxidase type D (dehydrogenase) in the intestine and other organs of the rat

Abstract: The work was aided by a grant from the Consiglio Nazionale delle Ricerche, Rome.

Cited by 188 publications

References 1 publication

Oxygen radicals in ulcerative colitis

Oxygen radicals in ulcerative colitis

Lack of conversion of xanthine dehydrogenase to xanthine oxidase during warm renal ischemia

Simulation of free radical reactions in biology and medicine: A new two-compartment kinetic model of intracellular lipid peroxidation☆

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