Genetic polymorphisms of human flavin monooxygenase 3 in sulindac-mediated primary chemoprevention of familial adenomatous polyposis.
OBJECTIVE
Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) effective in regressing adenomas in patients with familial adenomatous polyposis (FAP). However, a recent randomized trial showed that sulindac, when compared with placebo, failed to prevent the development of adenomatous polyps in genotypically positive but phenotypically negative FAP patients. The present study determined whether polymorphisms in the gene encoding flavin monooxygenase 3 (FMO3), a hepatic microsomal enzyme that inactivates sulindac, played a role in determining the efficacy of sulindac in preventing polyposis in this cohort of FAP patients.


METHODS
Genotyping was performed on seven established FMO3 polymorphisms previously shown to have functional relevance-M66I, P153L, E158K, V257M, E305X, E308G, and R492W-in 21 and 20 FAP patients, who received sulindac and placebo, respectively.


RESULTS
None of the 41 patients exhibited heterozygous or homozygous M66I and R492W variant alleles, or homozygous P153L, V257M, and E305X variant alleles. Among sulindac-treated patients who did not develop adenomas ("responders"), 4 (33%) were homozygous for E158K and 2 (17%) were homozygous for E308G variant alleles. In contrast, none of the patients on sulindac who developed adenomas ("nonresponders") exhibited homozygosity for either of the two variant alleles. In addition, polymorphisms in the E158K or E308G allele were associated with a significant reduction in mucosal prostanoid levels in patients treated with sulindac.


CONCLUSIONS
Polymorphisms in FMO3, particularly at the E158K and E308G loci, may reduce activity in catabolizing sulindac and result in an increased efficacy to prevent polyposis in FAP.
Hisamuddin
Irfan M
IM
Division of Digestive Diseases, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Wehbi
Mohammad A
MA
Chao
Ann
A
Wyre
Hadley W
HW
Hylind
Linda M
LM
Giardiello
Francis M
FM
Yang
Vincent W
VW
D011125:Adenomatous Polyposis Coli / Q000175:diagnosis / Q000201:enzymology* / Q000517:prevention & control*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018890:Chemoprevention; D015331:Cohort Studies; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D010105:Oxygenases / Q000235:genetics*; D010919:Placebos; D011110:Polymorphism, Genetic; D011453:Prostaglandins / Q000378:metabolism; D013467:Sulindac / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D010919:Placebos; D011453:Prostaglandins; D013467:Sulindac; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)