Phenotyping of Flavin-containing Monooxygenase using Caffeine Metabolism and Genotyping of FMO3 Gene in a Korean Population

초록

Flavin-containing Monooxygenase (FMO) is known to catalyze the oxidative metabolism of nitrogen-, sulfur- and phosphorus-containing compounds included in many clinically useful drugs, plant alkaloids and endogenous chemicals (Ziegler, 1980; 1988;1993; Cashman, 1995; Hodgson et al., 1995). In human, 5 isoforms (FMO1-5) have been found and the FMO3 is known to be the major form present in adult liver (Lomri et al., 1992; Dolphin et al., 1996; Overby et al., 1997) and is responsible for the FMO catalyzed drug oxidation in vivo. IN this connection, the oxidative metabolism of some clinically useful drugs (i. e., thiobenzamide, tamoxifen, olanzapine, clozapine, cimetidine, ranitidine, ketoconazole and methiamzole) as well as some food borne secondary and tertiary amines like trimethylamine have been reported to be catalyzed by FMO3. As these drugs are used clinically and as the pharmacokinetics of these drugs are dependent on the hepatic FMO3 activities, a non-invasive means of determining the FMO activity in vivo us needed for safe use of these drugs in human. In this connection, a recent study conducted in this laboratory has shown that production of theobromine (TB) from caffeine (CA) is catalyzed primarily by the FMO in human liver microsomes (Chung and Cha, 1997, Chung et al., 1998a). Utilizing this basic information, we were able to asses the in vivo FMO activity in human by taking the molar concentration ratio of TB/CA in urine in the Korean population (Chung et al, submitted to Clin. Pharm. Ther., 1998). Thus, in the present study, we have made an effort to understand the underlying reasons for the interpersonal differences observed for the in vivo FMO activity as determined by the urinary molar concentration ratio of TB/CA (coffee test) in another set of Korean population.