Xanthine Oxidase

Xanthine oxidase (XO) is an enzyme involved in the formation of uric acid in the body. XO inhibitors, such as allopurinol, have been the cornerstone of therapy for gout and hyperuricemia for years. Recent research has also demonstrated that XO-derived superoxide formation plays a pathogenetic role in a variety of diseases including inflammatory bowel disease, shock, acute respiratory distress syndrome and heart failure. The realization of the pathogenetic role of XO in these diseases opens the door for the development of novel, potent XO inhibitors for numerous additional disease indications.

XO and xanthine dehydrogenase (XD) are interconvertible forms of the same enzyme, known as xanthine oxidoreductase (XOR). The enzymes are molybdopterin-containing flavoproteins that consist of two identical subunits of approximately 145 kDa. XO (XOR) is widely distributed throughout various organs including the liver, gut, lung, kidney, heart, brain as well as the plasma. It is generally accepted that XO normally occurs in vivo as an NAD dependent cytosolic dehydrogenase enzyme (XD), incapable of the production of reactive oxygen species. Most investigators agree that XD activity is converted, by sulfhydryl oxidation or limited proteolysis, to an oxidase that produces superoxide and hydrogen peroxide. It is worthwhile to note, nevertheless, that both XO and XD can oxidize NADH, with the concomitant formation of reactive oxygen species. Physiologically, XO and XD participate in a variety of biochemical reactions including the hydroxylation of various purines, pterines and aromatic heterocycles, as well as aliphatic and aromatic aldehydes, thereby contributing to the detoxification or activation of endogenous compounds and xenobiotics. One of XOR’s primary roles is the conversion of hypoxanthine to xanthine and xanthine to uric acid. Inherited XOR deficiency leads to xanthinuria and a characteristic multiple organ failue syndrome characterized by the deposition of xanthine in various tissues.

Currently, the most widely accepted indication for the development of novel XO inhibitors is the treatment of hyperuricemia and gout. Gout is a common disease, which occurs in individuals who have high serum uric acid levels. Over time, a precipitation of monosodium urate monohydate crystals occurs in various tissues, followed by an inflammatory response.

Recent work has implicated a role for XO and XO-related oxidant species in the pathogenesis of CHF. In vitro studies in isolated hearts have demonstrated that the progressive development of heart failure is associated with increased myocardial XO levels, which contributes to an enhancement of oxidative stress in the heart. In a heart failure model induced by pacing in the dog, a four-fold increase in myocardial XO levels was found, with subsequent increases in oxidative stress in the heart. In a ligation-induced CHF model in the rat, an approximately 50% increase was noted. In CHF patients, elevated circulating uric acid levels have been noted as well as an increase in myocardial XO activity. There was a strong correlation between the levels of uric acid and the severity of chronic inflammation – as evaluated by plasma measurements of soluble ICAM-1, TNF-alpha, soluble TNF receptor 2 and E-selectin.