Effect of Grapefruit Juice on CYP1A2 Dependent Metabolism of Caffeine in Korean

한국인에서 CYP1A2의존성 Caffeine 대사에 대한 자몽과즙의 억제효과

Background : As caffeine is specifically N3-demethylated by CYP1A2, caffeine has been used as a metabolic probe to determine the relative CYP1A2 activity in human. Grapefruit juice has been demonstrated to inhibit mammalian cytochrome P450 enzymes like CYP3A4. Thus, the objective of this study was to determine whether the grapefruit juice will inhibit the CYP1A2 activity in unrelated healthy Korean subjects. Method : Volunteers(47 subjects) refraining from methylxanthine-containing foods or beverages were given a cup of coffee (110mg caffeine) at 8 a.m.. They voided urine at 12 a.m. and provided 1 hr urine sample at 1 p.m.. On the second day, the volunteers were given 500ml of grapefruit juice at 7 a.m. and at 8 a.m., they were given 1 cup of coffee. At 9 a.m. and 11 a.m., they were given 500ml of grapefruit juice again. Again, the volunteers voided urine at 12 a.m. and provided the 1 hr urine sample at 1 p.m. The caffeine metabolites present in the urine samples from both days were analyzed with HPLC. The relalive CYP1A2 activities in each individual were calculated by taking the molar concentration ratio of [paraxanthine +1,7-dimethylurate]/[caffeine]. Results : The basal CYP1A2 activity for all volunteers was $15.3{\pm}7.7$ and after taking the grapefruit juice, the CYP1A2 activity was decreased significantly to $10.3{\pm}6.2$ (Wilcoxon signed-rank test, p<0.0001). Upon intake of the grapefruit juice, the CYP1A2 activity was decreased in 39 volunteers but the CYP1A2 activity in 8 was increased slightly. The CYP1A2 activities of smokers either before or after the grapefruit juice intake were higher (Mann-Whitney U test, p<0.005) and thus, the induction of enzyme activity by cigarette smoking was confirmed. There were no significant differences in the fraction of CYP1A2 inhibition between the nonsmokers and smokers, and the fraction of CYP1A2 activity inhibition had no significant relationship with the basal activity. Conclusion : Intake of grapefruit juice will inhibit the CYP1A2 activity in man and will interfere with the metabolism of clinically useful drugs which are metabolized by CYP1A2. Therefore, in persons whose CYP1A2 activity is severely inhibited by grapefruit juice, taking drugs metabolized by CYP1A2 together with grapefruit juice could bring unexpected drug toxicity. Conversely, as the CYP1A2 is known to be involved in metabolic activation of procarcinogens belonging to aromatic amines (in cigarette) or heterocyclic amines (in broiled meats), taking grapefruit juice would lower the cancer susceptibility.

연구배경 : Caffeine은 대부분 CYP1A2에 의해 N3-demethylation되므로 개인의 CYP1A2 활성도를 측정하는 지표로 이용되고 있으며, 자몽과즙은 CYP3A4 등의 cytochrome P450을 억제하는 것으로 알려져 있다. 따라서 본 연구에서는 한국인에서 자몽과즙의 섭취가 CYP1A2의 활성도에 미치는 영향을 규명하고자 하였다. 방 법: 건강한 한국인 자원자 47명을 대상으로 caffeine 110mg을 함유한 커피를 투여한 후 4시간에서 5시간사이의 요중 caffeine 및 그 대사체를 HPLC로 분석하여 [paraxanthine +1,7-dimethylurate]/[caffeine]의 요중 몰 농도비로 CYPIA2의 활성도를 측정하고, 24시간 후에 같은 대상자들에게 같은 양의커피와 커피 투여 1시간 전, 1시간 후 및 3시간 후에'double strength 자몽과즙'을 500mL씩 총 1.5L를 마시게 한 후 같은 방법으로 CYP1A2의 활성도를 측정하였다. 결 과 : 연구에 참여한 대상자 47명 전체의 CYP1A2의 활성도는 평균활성도가 $15.3{\pm}7.7$에서 자몽과즙의 섭취에 의해 $10.3{\pm}6.2$로 $28.2{\pm}31.7%$(평균${\pm}$표준편차) 감소하였으며(p<0.0001), 대상자중 39명(83%)에서는 CYP1A2 활성도의 감소가 나타났으나 8명(17%)에서는 오히려 CYP1A2의 활성도가 증가하였다. 흡연자군에서 CYP1A2의 기저활성도 중앙값은 17.7로서 비흡연자군의 13.5보다 높았으며(Pi0.004) 자몽과즙의 섭취에 의한 CYP1A2활성도 감소분획은 두 군간에 의미있는 차이를 보이지 않아(p=0.314) 자몽과즙 섭취후에도 CYP1A2 활성도 중앙값은 흡연자군(13.4)이 비흡연자군(6.8)보다 훨씬 높았다. 결 론 : 자몽과즙의 섭취는 한국인에서 CYP1A2의 활성도를 억제하므로 CYP1A2에 의해 대사되는 약물을 자몽과즙과 함께 복용할 경우 그 약물의 대사가 억제됨으로써 개인에 따라 예상하지 못했던 약물 독성이 유발될 수 있으며, 다른 한편으로 자몽과즙의 섭취는 CYP1A2에 의해 활성화되어 생성되는 발암물질에 의한 암 발생을 억제하는 예방효과를 기대할 수 있을 것으로 사료된다.