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The in Vitro Inhibition of Xanthine Dehydrogenase by 8-Azaguanine^*

( Departments of Biochemistry and Medicine, College of Physicians and Surgeons, Columbia University, and Francis Delafield Hospital, New York 32, N.Y.)

8-Azaguanine was found to inhibit purified xanthine dehydrogenase in vitro; 50 per cent inhibition of the enzymatic activity occurred at the concentration of 5 x 10^-5 M 8-azaguanine. The inhibition was noncompetitive with regard to substrate. Kinetic studies indicate that 8-azaguanine manifests approximately one-half the affinity for the enzyme as does the substrate (K_i = 5.0 x 10^-5 M; K_s = 2.6 x 10^-5 M). One mole of 8-azaguanine combines with each mole of enzyme.

A hypothesis is proposed localizing a major pharmacological effect of 8-azaguanine to the induction of a guanine moiety deficiency by interference with xanthine oxidase, an enzyme postulated as catalyzing an essential reaction along one metabolic route leading to guanine moiety biosynthesis. This hypothesis is applied toward the integration of several previously reported findings.

^* This investigation was supported in part by research grants C 2046 and C 2332, from the National Cancer Institute of the National Institutes of Health, Public Health Service.

Received 12/ 4/55.