In vitro and in vivo inhibition of human flavin-containing monooxygenase form 3 (FMO3) in the presence of dietary indoles.
The effect of consumption of glucosinolate-containing Brussels sprouts on flavin-containing monooxygenase functional activity in humans was investigated in 10 healthy, male, non-smoking volunteers. After a 3-week run-in period, 5 volunteers continued on a glucosinolate-free diet for 3 weeks (control group), and 5 others consumed 300 g of cooked Brussels sprouts per day (sprouts group). Human flavin-containing monooxygenase activity was measured by determining the levels of urinary trimethylamine and trimethylamine N-oxide. In the control group similar trimethylamine to trimethylamine N-oxide ratios were observed, while in the sprouts group the trimethylamine to trimethylamine N-oxide ratios were increased 2.6- to 3.2-fold, and thus flavin-containing monooxygenase functional activity was decreased significantly. To investigate the molecular basis for the in vivo inhibition of functional human flavin-containing monooxygenase activity, in vitro studies were carried out examining the effect of acid condensation products of indole-3-carbinol, anticipated to be formed after transit of Brussels sprouts through the gastrointestinal system, on the prominent cDNA-expressed human flavin-containing monooxygenase form 3 enzymes. Two indole-containing materials were observed to be potent inhibitors of human flavin-containing monooxygenases, having Ki values in the low micromolar range. The results suggested that acid condensation products expected to be formed upon transit of Brussels sprouts materials through the gastrointestinal system were potent competitive inhibitors of human flavin-containing monooxygenase form 3 enzymes. The findings indicate that daily intake of Brussels sprouts may lead to a decrease in human flavin-containing monooxygenase activity, and this may have consequences for metabolism of other xenobiotics or dietary constituents.
Cashman
J R
JR
Human Biomolecular Research Institute, San Diego, CA 92121, USA. ledcash@aol.com
Xiong
Y
Y
Lin
J
J
Verhagen
H
H
van Poppel
G
G
van Bladeren
P J
PJ
Larsen-Su
S
S
Williams
D E
DE
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D001937:Brassica / Q000737:chemistry*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018592:Cross-Over Studies; D004032:Diet; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D058619:Maltose-Binding Proteins; D008744:Methylamines / Q000652:urine; D010105:Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000975:Antioxidants; D002352:Carrier Proteins; D007211:Indoles; D058619:Maltose-Binding Proteins; D008744:Methylamines; C016517:indole-3-carbinol; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine