Elevated uric acid levels (hyperuricemia), which form crystals in the joints, may lead to gout, which is associated with chronic kidney disease. Allopurinol is the major pharmacologic agent used for the treatment and prevention of hyperuricemia and gout, as well as other diseases associated with metabolic syndrome. Recent studies involving a large patient cohort challenge the widely accepted pharmacologic mechanism of action of allopurinol and its major active metabolite, oxypurinol, as pure inhibitors of xanthine oxidase-mediated synthesis of uric acid. In particular, our data suggest a major role of the ATP Binding Cassette Transporter, Breast Cancer Resistance Protein (BCRP or ABCG2 in this proposal) in response to allopurinol. In the first genomewide association study, GWAS, of allopurinol response, we observed a single locus, in ABCG2, strongly associated with response to allopurinol in approximately 1492 patients of European ancestry (p = 1.9 x 10-9). Moreover, in follow-up studies in cells we observed that allopurinol and oxypurinol are excellent substrates of ABCG2, suggesting that the transporter plays a role in the drugs'disposition and effects. Importantly, we also observed that both compounds inhibit uric acid reabsorptive transporters in the renal proximal tubule. The ABCG2 locus identified in our GWAS included the nonsynonymous variant, Q141K (rs2231142), which is known to have reduced transport function due to reduced protein expression. In the proposed studies, we will test the hypothesis that ABCG2-Q141K results in reduced renal clearance of allopurinol and oxypurinol;in turn, the reduced renal clearance results in reduced response to the drugs because of decreased inhibition of uric acid reabsorptive transporters in the renal tubule. Our proposed research involves integrated cellular studies (Aim 1) ascertaining the kinetics of allopurinol, oxypurinol and uric acid with major renal uric acid transporters;and intense phenotyping of patients with hyperuricemia on allopurinol (Aim 2), which includes both pharmacokinetic and pharmacodynamic analyses. Finally, we include an aim (Aim 3) that validates and extends our findings to other major ethnic and racial populations. In particular, in a large meta-analysis we will validate ABCG2 as a critical gene involved in allopurinol pharmacologic mechanism and discover additional loci in individuals from multiple racial and ethnic groups. The proposed studies will add new knowledge to understanding the pharmacological mechanisms of action of allopurinol and oxypurinol and will greatly add to our understanding of genetic factors that lead to variation in response to the drug. Importantly, the studies will lead to the use of genetic information in selection of medications for the treatment of patients with gout.
Allopurinol is the major medication used to treat gout, a major health problem worldwide, which is associated with heart disease and obesity. Unfortunately, because of genetic factors many people do not respond to the drug. This research will advance our understanding of the mechanisms responsible for allopurinol's beneficial effects using computational and experimental studies in cells and in people with gout.
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