Guanines, xanthine oxidase inhibition

As indicated in Fig. 25-18, free adenine released from catabolism of nucleic acids can be deaminated hydrolytically to hypoxanthine, and guanine can be deaminated to xanthine.328 The molybdenum-containing xanthine oxidase (Chapter 16) oxidizes hypoxanthine to xanthine and the latter on to uric acid. Some Clostridia convert purine or hypoxanthine to xanthine by the action of a selenium-containing purine hydroxylase.3283 Another reaction of xanthine occurring in some plants is conversion to the trimethylated derivative caffeine. 328b One of the physiological effects of caffeine in animals is inhibition of pyrimidine synthesis.329 However, the effect most sought by coffee drinkers may be an increase in blood pressure caused by occupancy of adenosine receptors by caffeine.330... 

Treatment the drug that most effectively inhibits the formation of uric acid is allopurinol, a competitive inhibitor of xanthine oxidase. Hypoxanthine and xanthine are excreted during allopurinol therapy. Allopurinol, as with guanine and hypoxanthine, can be converted to its ribonucleotide form by HGPRT. Reducing the formation of uric acid with allopurinol relieves the symptoms of gout and decreases the possibility that uric acid kidney stones will form. 

Methoxy-, 6-ethoxy-, and 6-methylthio-9-ribofuranosyl-8-azapurines turned out to be substrates for adenosine kinase, and the first two examples were bound by adenosine deaminase. Their cytotoxic action was attributed to affinity for the kinase. 6-Imino-9-phenyl-l,6-dihydro-8-azapurine was found to be an efficient inhibitor of adenosine deaminase and guanine deaminase. Xanthine oxidase was inhibited by both this compound and 9-aryl-8-azapurin-6-ones. ° ... 

A set of 4-amino-3-aryltriazoles, each one further substituted by a 5-amide, -ester, or -nitrile group, inhibited these enzymes adenosine deaminase, guanine deaminase, and xanthine oxidase. Structure-action relationships were discussed (79MI1 85FES73). 

Further in vitro studies using a lung cancer cell line (A549) demonslrated that febuxostat (16 xM for 3h) completely inhibited xanthine oxidase activity without affecting the activities of adenosine deaminase, purine nucleoside phosphorylase, adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, pyrimidine -nucleoside phosphorylase, or guanase. ... 

According to the experiments described in table 3 the addition of allopurinol does effect neither the inhibition of the hypoxanthine-guanine phosphoribosyltransferase by 6-MP nor the conversion of 6-MP to thioinosinic acid by the same enzyme. It is unprobable that this is due to a lack of xanthine oxidase in the cells investigated, because, in the same cell-free system the inhibitory effect of 6-MP on the formate activation was markedly increased by allopurinol (fig.6). 

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