Effect of TEI-6720, a Xanthine Oxidase Inhibitor, on the Nucleoside Transport in the Lung Cancer Cell Line A549

Abstract

To examine the effect of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (TEI-6720), an inhibitor of xanthine oxidase, on purine metabolism in the lung cancer cell line A549, the activities of adenosine deaminase, purine nucleoside phosphorylase, adenine phosphoribosyltransferase, hypoxanthine guanine phosphoribosyltransferase, xanthine oxidase, and guanase together with pyrimidine nucleoside phosphorylase were measured with or without the addition of TEI-6720, and the extracellular concentrations of hypoxanthine, xanthine, inosine, uracil, and uridine were measured after the addition of inosine or uridine to the incubation medium with or without TEI-6720. Moreover, the Na-indepenent nucleoside transport was determined in A549 cells with or without TEI-6720. TEI-6720 inhibited the activity of xanthine oxidase in A549 cells, but did not affect other enzymes. During incubation, TEI-6720 not only prevented a decrease in the inosine concentration in inosine-containing medium, but also a decrease in the uridine concentration in uridine-containing medium. Furthermore, the Na-independent transport of uridine was inhibited by TEI-6720 with a K_i value of 4.1 μmol/l. These results indicate that TEI-6720 is an inhibitor of the Na-independent nucleoside transport of uridine and inosine, as well as xanthine oxidase.

Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase

“…In the present study, febuxostat at concentrations up to 100 AM did not show significant effect on the purine or pyrimidine metabolic enzymes tested. A report by Yamamoto and colleagues using A549 cells, a human type II alveolar epithelial cell line, revealed that febuxostat had no effect on guanine deaminase, HGPRT or PNP at concentrations up to 16 AM (Yamamoto et al, 2000). Yamamoto et al also reported that febuxostat exerted no effect on the purine metabolic enzymes, adenine deaminase and adenine phosphoribosyl transferase, or on pyrimidine nucleoside phosphorylase, at concentrations up to 16 AM (Yamamoto et al, 2000).…”

“…A report by Yamamoto and colleagues using A549 cells, a human type II alveolar epithelial cell line, revealed that febuxostat had no effect on guanine deaminase, HGPRT or PNP at concentrations up to 16 AM (Yamamoto et al, 2000). Yamamoto et al also reported that febuxostat exerted no effect on the purine metabolic enzymes, adenine deaminase and adenine phosphoribosyl transferase, or on pyrimidine nucleoside phosphorylase, at concentrations up to 16 AM (Yamamoto et al, 2000). This current report and previously published data strongly supports the selectivity of febuxostat in the inhibition of XO activity.…”

Efficacy and safety of febuxostat in patients with hyperuricemia and gout

“…Unlike allopurinol (and its active metabolite oxypurinol), febuxostat is not a purine analog and inhibits only xanthine oxidase/dehydrogenase, not other enzymes in the purine and pyrimidine metabolic pathways [Edwards, 2009;Khosravan et al 2006b;Okamoto et al 2003]. In vitro studies have demonstrated how febuxostat potently and selectively inhibits human xanthine oxidase activity, whereas the activity of other enzymes, such as purine nucleoside phosphorylase, adenosine deaminase, and pyrimidine nucleoside phosphorylase, are affected by less than 4% [Yamamoto et al 2000].…”

Management of Chronic Hyperuricemia with Febuxostat

“…24 Febuxostat requires no conversion to an active form and, since it is structurally unrelated to purine or pyrimidines, is more selective for xanthine oxidase; it therefore does not interfere with other enzymes in the purine metabolism pathway. 25,26 Febuxostat inhibits both the reduced and oxidized forms of xanthine oxidase by binding with high affinity in a narrow channel leading to the molybdenum center of the enzyme and essentially obstructing substrate binding. 24 This enhanced mechanism produces more sustained reductions in sUA levels compared to allopurinol.…”