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Gout Remedy Report

Gout Remedy Report by Joe Barton

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While MAO does not appear to be a major catalyst in the metabolism of amine-containing drugs, it can contribute. The extent to which it does remains to be determined.

5.05.2.4 Xanthine Oxidoreductase

Xanthine oxidoreductase is a complex homodimeric 300 kDa cytosolic enzyme. Each subunit contains a molybdopterin cofactor, FAD, and two nonidentical iron-sulfur centers.

It is widely distributed, and exists in two interconvertible forms in mammals: xanthine dehydrogenase and xanthine oxidase. Xanthine dehydrogenase predominates in vivo, while xanthine oxidase is the form that is generally isolated.186-188 Maximum concentrations of xanthine oxidoreductase have been found in liver, intestine, and lactating mammary gland.189 In patients with liver disease, xanthine oxidoreductase activity has been found to be 10-20-fold higher than that found in healthy liver tissue.190

Its primary role appears to be in the metabolism of purines (e.g., it catalyzes the sequence of oxidations that convert hypoxanthine (161) to xanthine (162), then to uric acid (163) (Scheme 17)). Excess uric acid production can lead to flare-ups of symptomatic gout. One of the effective treatments for gout is the administration of allopurinol (164). Allopurinol is both a competitive inhibitor of xanthine oxidoreductase and a substrate, as xanthine oxidoreductase slowly oxidizes 164 to alloxanthine (165) (eqn [48]). Since 165 is also an inhibitor of xanthine oxidoreductase, the therapeutic effectiveness of 164 is not significantly compromised by its conversion to 165. However, if 164 and the anticancer agent 6-mercaptopurine (166) are coadministered, inhibition of xanthine oxidoreductase can be problematic. If the extensive first-pass metabolism of 166 to 6-mercaptouric acid (167), catalyzed by xanthine oxidoreductase (eqn [49]), is inhibited by 164, it can result in potentially toxic plasma concentrations of 166 fivefold higher than normal.191

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