Oxidation of Selected Pteridine Derivatives by Mammalian Liver Xanthine Oxidase and Aldehyde Oxidase

Abstract

Considerable information is available concerning the oxidation of pteridine derivatives by bovine milk xanthine oxidase, but few investigations have been carried out on the oxidation of such compounds by mammalian liver xanthine oxidase and the related aldehyde oxidase. Xanthine oxidase, obtained from rat liver, oxidizes a variety of substituted amino‐ and hydroxypteridines in a manner identical to that previously observed for milk xanthine oxidase. For example, 2‐aminopteridine and its 4‐ and 7‐hydroxy derivatives were oxidized efficiently to 2‐amino‐4, 7‐dihydroxypteridine (isoxan‐thopterin) by the rat liver enzyme, and 4‐aminopteridine and its 2‐and 7‐hydroxy derivatives were oxidized to 4‐amino‐2, 7‐dihydroxypteridine. 4‐Hydroxypteridine and the isomeric 2‐ and 7‐hydroxypteridines were oxidized by rat liver xanthine oxidase to 2,4,7‐trihydroxypteridine. Rabbit liver aldehyde oxidase, but not rat liver xanthine oxidase, was able to catalyze the oxidation in position 7 of 2,4‐diaminopteridine and its 6‐methyl and 6‐hydroxymethyl derivatives. 2‐Aminopteridine and 4‐aminopteridine were both oxidized to the corresponding 7‐hydroxy derivatives in the aldehyde oxidase system; 2‐amino‐4‐hydroxypteridine appeared to be a minor product in the oxidation of 2‐aminopteridine by rabbit liver aldehyde oxidase. Both aldehyde oxidase and xanthine oxidase were able to catalyze the oxidation of 2‐amino‐6,7‐disubstituted pteridines to the corresponding 4‐hydroxy derivatives; 4‐hydroxy‐6,7‐disubstituted pteridines were oxidized in position 2 by both enzymes. 4‐Amino‐6,7‐disubstituted pteridines were not oxidized by either enzyme. 2‐Amino‐4‐methylpteridine was oxidized in position 7 by aldehyde oxidase but was not an effective substrate for xanthine oxidase; 2‐hydroxypteridine and 7‐hydroxypteridine were not oxidized to a detectable extent by aldehyde oxidase. All oxidations mediated by xanthine oxidase were strongly inhibited by allopurinol (4‐hydroxy‐pyrazolo[3,4‐d]pyrimidine), and all oxidations mediated by aldehyde oxidase were inhibited by menadione (2‐methyl‐1,4‐naphthoquinone). Rat liver xanthine oxidase and, to a lesser extent, rabbit liver aldehyde oxidase were inhibited by 4‐chloro‐6,7‐dimethylpteridine; 2‐amino‐3‐pyrazinecarboxylic acid inhibited xanthine oxidase but not aldehyde oxidase. The oxidations of 2‐ and 4‐aminopteridines by aldehyde oxidase resulted in concomitant reduction of cytochrome c.