Differential Inhibition of Flavin-Containing Monooxygenase (FMO) with Grapefruit Juice

초록

FMO is known to be involved in the metabolism of many clinically useful drugs and xenobiotics. The objectives of this study is to investigate inhibitory effect of driking grapefruit juice on the human FMO activity measured by the productions of theophylline(TP) and theobromine(TB) from caffeine(CA). After a cup of coffee (110mg caffeine), 1hr urine samples (between 4 and 5hr) were collected from 47 Korean volunteers and the urinary CA metabolites were analyzed. As an index of the human FMO activity, we have used the ratio of urinary (TB+TP)/(CA). Probit analysis of the obtained FMO activity showed a bimodal distribution and the volunteers were divided into poor(PM) and extensive metabolizers (EM). The same Volunteers were given 500ml of grapefruit juice at 1hr before, and at 1 and 3hr after the coffee and their FMO activity was measured again from the collected urine samples. Results activities were measured again from the collected urine the PM group, it was significantly inhibited in the EM group (Wilcoxonsigned rank test; P<0.0001). In support of these in vivo human data, in vivo preliminary studies conducted using rat and human liver microsomes, we found that pure naringin, thought to be contained in grapefruit juice, inhibited the microsomal FMO activity measured by using the production of S-oxide metabolite from thionbenzamide and the production of TB and TP from CA. We concluded that narigin contained in grapefruit juice may inhibit the FMO activity. Thus drinking grapefruit juice may prolong the half-life of drugs metabolized by FMO.