Genetic polymorphisms of flavin monooxygenase 3 in sulindac-induced regression of colorectal adenomas in familial adenomatous polyposis

Abstract

Sulindac is a nonsteroidal antiinflammatory drug with a chemopreventive effect in patients with familial adenomatous polyposis (FAP). In vivo, the active form of sulindac is sulindac sulfide, which is inactivated by the hepatic microsomal enzyme, flavin monooxygenase 3 (FMO3). In humans, numerous polymorphisms exist in FMO3, which alter enzymatic activity and subsequent substrate metabolism. We recently showed that certain polymorphic forms of FMO3 with reduced activity were associated with a more favorable response to sulindac in preventing the formation of adenomas in patients with FAP without polyps at baseline. Here, we determined whether these FMO3 polymorphisms correlated with the ability of sulindac to regress polyposis in patients with FAP who had polyps prior to treatment. Nineteen patients were treated with 150 mg sulindac twice a day for 6 months. The size and number of polyps in each patient was assessed at baseline (prior to the administration of sulindac), and at 3 and 6 months. Genotyping was done on seven established FMO3 polymorphisms with functional significance-M66I, E158K, P153L, V257M, E305X, E308G, and R492W. Statistical analyses were done with Wilcoxon rank sum test. Of the loci examined, only E158K and E308G showed polymorphic changes. Six patients exhibited polymorphisms in both E158K and E308G loci and were designated as genotype combination 1. The remaining patients were designated as genotype combination 2. Over the course of treatment, patients with genotype combination 1 had a greater reduction in both the size and number of polyps than those with genotype combination 2. These results suggest that combined polymorphic changes in the E158K and E308G alleles may protect against polyposis in patients with FAP treated with sulindac.

Figure 1

The reduction in polyp size from baseline in patients with genotype combinations 1 and 2 over the 6-month course of sulindac treatment. Medians of polyp size for patients with genotype combination 1 (solid line) and 2 (dashed line) over the course of treatment with sulindac are shown. The vertical bars span between the first and third quartiles.

Figure 2

The reduction in polyp number from baseline in patients with genotype combinations 1 and 2 over the 6-month course of sulindac treatment. Medians of polyp number for patients with genotype combination 1 (solid line) and 2 (dashed line) over the course of treatment with sulindac are shown. The vertical bars span between the first and third quartiles.