Xanthine oxidase liver

Stirpe, F. and Della Corte, E. (1969). The regulation of rat liver xanthine oxidase. Conversion in vitro of the enzyme activity from dehydrogenase (type D) to oxidase (type O). J. Biol.Chem. 244, 3855-3863. 

Guerciohni R, Szumlanski C, Weinshilboum RM Human liver xanthine oxidase nature and extent of individual variation. Chn Pharmacol Ther 50 663-672, 1991 Guisti P, Ducic I, Puia G, et al Imidazenil a new partial positive allosteric modulator of gamma-amniobutyiic acid (GABA) action of GABAa receptors. J Pharmacol Exp Ther 266 1018-1028, 1993... 

The first hint of an essential role of molybdenum in metabolism came from the discovery that animals raised on a diet deficient in molybdenum had decreased liver xanthine oxidase activity. There is no evidence that xanthine oxidase is essential for all life, but a human genetic deficiency of sulfite oxidase or of its molybdopterin coenzyme can be lethal.646,646a,b The conversion of molybdate into the molybdopterin cofactor in E. coli depends upon at least five genes.677 In Drosophila the addition of the cyanolyzable sulfur (Eq. 16-64) is the final step in formation of xanthine dehydrogenase.678 It is of interest that sulfur (S°) can be transferred from rhodanese (see Eq. 24-45), or from a related mercaptopyruvate sulfurtransferase679 into the desulfo form of xanthine oxidase to generate an active enzyme.680... 

The cofactors of both xanthine and aldehyde oxidases belong to the LMoVI(S)(0) subfamily (see Section IV). However, inactive dioxo forms, LMovi(0)2, of both xanthine and aldehyde oxidase are known. These dioxo forms do not catalyze oxidation of the respective substrates of these enzymes. The Mov/Molv redox potential for the inactive bis(oxido) form of xanthine oxidase differs from the oxido-sulfido form by -30 mV (bovine xanthine oxidase) and -lOOmV (chicken liver xanthine oxidase) [91]. Although the difference is small, given the xanthine/uric acid reduction potential (-360 mV), it is possible that the Mov/MoIV couple (-433 mV) of the chicken-liver xanthine oxidase bis(ox-ido) form impedes the effective oxidation of xanthine for redox reasons alone. However, the bis(oxido) form of bovine xanthine oxidase (with a reduction potential of -386 mV) should be able to oxidize xanthine, since the redox potential, and hence the thermodynamic driving force, is sufficient for activity [91,92,99]. As substrate oxidation does not occur, the chemical differences between the bis(oxido) and oxido-sulfido (Movl) forms must be critical to the dramatic difference in activity (see Section VI.E.l). 

Allopurinol (tablet) 15 70 Intestine + liver (xanthine oxidase)... 

It therefore appears that newborn infants have a greater requirement for maternal xanthine oxidase in the first few days after birth and it has been proposed that the high xanthine oxidase levels in colostrum may be to effect maximum absorption of dietary iron from the underdeveloped infant gut [93, 97], Furthermore, studies in the mouse have shown that liver xanthine oxidase is not present at birth, but is only apparent after 3 weeks, whereas the main isozyme of aldehyde oxidase can be detected in the 20-day foetus [98]. 

Using tungsten as a molybdenum antagonist, Higgins etal. (1956) demonstrated a 95-97% loss in rat intestine and liver xanthine oxidase activity, but without any notable adverse effect on the animals. However, in chicks - which use uric acid as the primary route of nitrogen excretion - oral administration of tungsten decreased urinary excretion of uric acid and caused a rise in fecal xanthine and hypoxanthine output, a reduction in growth, and an increase in mortality. 

Some oxidations are mediated by hepatic enzymes localized outside the microsomal system. Alcohol dehydrogenase and aldehyde dehydrogenase, which catalyse a variety of alcohols and aldehydes such as ethanol and acetaldehyde, are found in the soluble fraction of the liver. Xanthine oxidase, a cytosolic enzyme mainly found in the liver and in small intestine, but also present in kidneys, spleen and heart, oxidizes mercaptopurine to 6-thiouric acid. Monoamine oxidase, a mitochondrial enzyme found in liver, kidney, intestine and nervous tissue, oxidatively deanoinates several naturally occurring amines (catecholamines, serotonin), as well as a number of drugs. 

Febuxostat (1) inhibits bovine milk xanthine oxidase and mouse and rat liver xanthine oxidase/xanthine dehydrogenase with ICso values of 1.4, 1.8, and 2.0 nM, respectively ICso values obtained for allopurinol (2) for the same substance were 1700, 380, and 1100 nM, respectively. As shown in Table 1, febuxostat is the most potent inhibitor against xanthine oxidase. ... 

When the plasma iron-binding capacity of rats is saturated by an intravenous infusion of iron, the further administration of iron causes the metal to be deposited in the liver. The liver iron is tightly bound and cannot be released into the circulation. Similar observations were made in patients with spontaneous hemochromatosis. In these individuals a large amount of the intestinally absorbed iron goes directly to the liver without appearing in the plasma, suggesting that the iron that is not bound to transferrin finds its way to the liver and remains trapped there. Whether low liver xanthine oxidase activity or low plasma levels of transferrin could play a role in the pathogenesis of hemochromatosis remains to be seen [38]. 

BIOCHEMICAL MECHANISMS FOR SEX SPECIFIC DIFFERENCES OF RAT LIVER XANTHINE OXIDASE... 

Xanthine oxidase (EC 1.2.3.2) catalyzes the irreversible oxidation of hypoxanthine and xanthine to uric acid. Recently, we have shown that rat liver xanthine oxidase enzyme activity is, in part, dependent on both age-and sex-specific differences. Immaturity in both sexes, adult females and pubertal male castrates demonstrate a basal or feminine pattern of enzyme activity. Androgen is required in the pubescent period for the full expression of hepatic xanthine oxidase activity in the adult male. The effect of androgen exposure on hepatic enzyme activity, however, remains speculative. 

The purification scheme for rat liver xanthine oxidase was modified from the procedure described by Johnson, et al, and is shown in Table 1. Antisera was prepared in adult New Zealand white rabbits immunized with purified xanthine oxidase emulsified in Freund s... 

Table 1. Purification of Crude Rat Liver Xanthine Oxidase... 

Figure 1. PAGE of purified rat liver xanthine oxidase. (A) Coomassie blue staining. (B) Enzyme specific stain. (C) Coomassie blue stain after Sephacryl S-300 showing protein contamination (arrow).

Figure 5. Sex differences in the level of rat liver xanthine oxidase. Mean SD. Number of rats in parenthesis.

We have shown that adult rat liver xanthine oxidase exhibits sexual dimorphism. Males have greater enzyme activity by comparison to females. The increased enz3mie activity in the male corresponds to a greater mass of xanthine oxidase protein. Immature animals of both sexes have similar enzyme activity. 

Sex steroid and drug metabolizing enzymes in adult rat liver also conform to a pattern of activity consistent with sexual dimorphism. The sexual dimorphism of these enzymes has been shown to arise as a result of exposure to testicular androgen in the neonatal period. Since rat liver xanthine oxidase also exhibits sexual dimorphism in adult animals, the involvement of testicular androgen in the neonatal period as a mechanism for the observed sex differences in the adult was studied. 

In conclusion, the sexual dimorphism observed for rat liver xanthine oxidase activity in the male appears to result from the effect of androgen exposure in the neonatal period. This imprinting phenomenon is complete by four days of age and does not require an intact pituitary in the presence of androgen replacement for full expression of adult sexual dimorphism. The adult female is unresponsive to androgen therapy and hypophysectomy. In the female, this unresponsiveness may result because of the lack of androgen exposure in the neonatal period. 

His urinary excretion was normal for adenine (1,73 mg/ day) and for guanine (0,93 mg/day). We dit not find any measurable amount of 8 hydroxy-7 methyl guanine in daily urine but a concomitant increase of 7"methyl guanine (9 10 mg/day control 6,9 mg/day). SKUPP and AYVAZIAN (1969) have demonstrated that 8 hydroxy-7 methyl guanine is the product of oxidation ofT-methyl guanine but only by human liver xanthine oxidase. This xanthinuric man has a family, but up to now we have only seen one of his sisters who also has xanthinuria. 

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