20096
document
Genetic polymorphisms of human flavin monooxygenase 3 in sulindac-mediated primary chemoprevention of familial adenomatous polyposis . PURPOSE 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 . EXPERIMENTAL DESIGN 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 .
20097
Intervention_Pharmacological
sulindac-mediated
20098
Intervention_Pharmacological
Sulindac
20099
Intervention_Pharmacological
sulindac
20100
Intervention_Control
placebo
20101
Intervention_Pharmacological
sulindac
20102
Intervention_Pharmacological
sulindac
20103
Intervention_Pharmacological
sulindac
20104
Intervention_Control
placebo
20105
Intervention_Pharmacological
sulindac-treated
20106
Intervention_Pharmacological
sulindac
20107
Intervention_Pharmacological
sulindac
20108
Outcome_Physical
heterozygous or homozygous M66I and R492W variant alleles , or homozygous P153L , V257M , and E305X variant alleles
20109
Outcome_Physical
homozygous for E158K
20110
Outcome_Physical
homozygous for E308G variant alleles
20111
Outcome_Physical
homozygosity
20112
Outcome_Physical
mucosal prostanoid levels