Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol

Abstract

The prototypical xanthine oxidase (XO) inhibitor allopurinol, has been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades. More recent data indicate that XO also plays an important role in various forms of ischemic and other types of tissue and vascular injuries, inflammatory diseases, and chronic heart failure. Allopurinol and its active metabolite oxypurinol showed considerable promise in the treatment of these conditions both in experimental animals and in small-scale human clinical trials. Although some of the beneficial effects of these compounds may be unrelated to the inhibition of the XO, the encouraging findings rekindled significant interest in the development of additional, novel series of XO inhibitors for various therapeutic indications. Here we present a critical overview of the effects of XO inhibitors in various pathophysiological conditions and also review the various emerging therapeutic strategies offered by this approach.

Fig. 1

Schematic diagram of the purine degradation pathway.

Fig. 2

Crystal structure of the xanthine dehydrogenase dimer divided into the three major domains and two connecting loops. The two monomers have symmetry related domains in the same colors, in lighter shades for the monomer on the left and in darker shades for the monomer on the right. From the N to the C terminus, the domains are the iron/sulfur-center domain (residues 3–165; red), the FAD domain (residues 226–531; green), and the molybdopterin center (Mo-pt) domain (residues 590–1331; blue). The loop connecting the iron/sulfur domain with the FAD domain (residues 192–225) is shown in yellow, the one connecting the FAD domain with the Mo-pt domain (residues 537–589) is in brown, and the N and C termini are labeled. The FAD cofactor, the two iron/sulfur centers, the molybdopterin cofactor, and the salicylate also are included (Enroth et al., 2000). Copyright © 2000 National Academy of Sciences (Washington, DC). Reproduced with permission.

Fig. 3

Chemical structures of selected xanthine oxidase inhibitors.

Fig. 4

Ischemia-reperfusion injury hypothesis. During the course of ischemia, transmembrane ion gradients are dissipated, allowing cytosolic concentrations of calcium to rise, which in turn, activates protease that irreversibly converts XDH, predominant in vivo, into XO. At the same time, cellular ATP is catabolized to hypoxanthine, which accumulates. During the reperfusion, XO using readmitted oxygen and hypoxanthine generates superoxide and hydrogen peroxide. Scheme derived from Granger et al. (1981, and McCord (1985).

Fig. 5

XOR is up-regulated in patients with heart failure. A, representative Western blot of myocardial extracts from patients with end-stage idiopathic dilated cardiomyopathy (CM) and patients with normal cardiac function (NL) probed with monoclonal anti-XDH antibody. Bands corresponding to both XDH (145 kDa) and XO (125 and 85 kDa). B, densitometry depicting the average XDH/XO signal from all patients. The total XDH/XO signal is increased by 60% in idiopathic dilated cardiomyopathy. *, P < 0.05 by Student’s unpaired t test. Reprinted from Cappola et al. (2001), with permission from Lippincott Williams & Wilkins (Philadelphia, PA).

Fig. 6

Serum uric acid (UA) levels and survival in CHF patients. A recent study in 294 chronic heart failure patients indicates a graded relationship between serum uric acid levels and survival. The plots show Kaplan-Meier survival curves and hazard ratios for different serum uric acid levels. Patients with normal UA (400 μM) had best survival (at 12 months, 93%) compared with patients with UA between 401 and 600 μM [87%, risk ratio [RR] 1.76 (1.11 to 2.78)], patients with UA between 601 and 800 μM [RR 6.27 (3.73 to 10.54)], and patients with UA >800 μM [17%, RR 18.53 (9.18 to 37.42)]. Reprinted from Anker et al. (2003), with permission from Lippincott William & Wilkins.