Determination of Flavin-containing Monooxygenase (FMO) activity using human caffeine metabolism and differential inhibition of FMO activity with grapefruit Juice

초록

Flavin-containing monooxygenase (FMO) is known to be involved in the metabolism of many clinically useful drugs. In preliminary studies using rat and human liver microsomes, we found that the productions of theophylline(TP) and theobromine(TB) from caffeine(CA) are catalyzed by FMO. Thus, using the ratio of urinary (TP+TB)/(CA) as an index of the FMO activity. After a cup of coffee (110mg caffeine), 1hr urine samples collected and the urinary CA metabolites were analyzed. Probit analysis of the obtained FMO activity showed a bimodal distribution (break point at 2.26) and this indicated that the volunteers could be phenotyped into poor(PM) and extensive metabolizers (EM). Volunteers were given 500ml of grapefruit juice at 1hr before, and at 1 and 3hr after the coffee and the FOM activity was measured again from the collected urine samples. While the FMO activity in the PM group was not inhibited, it was significantly inhibited in the EM group (Wilcoxon signed rank test; P<0.0001). Thus, for patients with high FMO activity and taking drugs metabolized by FMO, drinking grapefruit juice may inhibit the FMO activity and lead to increased drug levels in blood.