간에서 FMO에 의한 카페인 대사 연구

초록

Caffeine (CA) is N-demetylated to theobromine (TB), paraxanthine (PX), and theophylline (TP) by rat and human liver microsomes. The optimal pHs for the formation of TB, PX, and TP from CA by rat liver microsomes are 7.4 (most), 8.2 (minor) and 8.6 (moderate). At pH 7.4, PX is the primary metabolite formed and makes up 48% of the CA metabolites generated. In the presence of SKF525A, an inhibitor of P450 (CYP), the rates of TB, PX and TP production are inhibited by 32%, 68% and 42%, respectively. Alternatively, in the presence of methimazole, an inhibitor of flavin-containing monooxygenase (FMO), the rates of TB, PX and TP production are inhibited by 66%, 48% and 73%, respectively. In the presence of both SKF525A and methimazole, they are inhibited by 95%, 84% and 94%, respectively. With human liver microsomes, the CA is metabolized faster but is inhibited more extensively either by SKF525A (PX production) or by methimazole (TB production). Alternatively, when CA is metabolized at pH 8.6, the optimal pH of FMO catalyzed reaction, the rates of TB and TP formation are increased but the rate of PX production is decreased. Furthermore, at pH 8.6 and in the presence of methimazole, the rates of TB and TP formation are decresed by 82% and 95%, respectively. These results indicate that the FMO is responsible primarily for productions of TB and TP while CYP is for PX formation. This is the first report showing that FMO is involved in the oxidative metabolism of CA and catalyzes the formations of TB and TP.