Kim Doyun, Zheng Yu Fen, Min Jee Sun, Park Jung Bae, Bae Soo Hyeon, Yoon Kee Dong, Chin Young-Won, Oh Euichaul, Bae Soo Kyung
College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, 420-743, Republic of Korea.
Department of Pharmacology, College of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 137-701, Republic of Korea.
Toxicol Lett. 2016 Sep 30;259:1-10. doi: 10.1016/j.toxlet.2016.07.108. Epub 2016 Jul 25.
We evaluated in vitro, the potential of the six pairs of ginsenoside isomers, stereoisomers at the chiral carbon on position 20, to inhibit the enzymatic activity of several UDP-glucuronosyltransferase (UGT) isoenzymes, major players in the human phase II drug metabolism. The results show that the tested six pairs of ginsenoside isomers exhibited stereoselective inhibitory effects of varying degrees on the ten UGT isoenzymes explored. Of the tested twelve stereoselective ginsenosides, 20(R)-Rg3 had the strongest inhibitory effect on the UGT1A8 isoform with the lowest IC50 value of 5.66±1.04μM. On the other hand, the (S)-isomers of Rg3 and Rh2 also exerted remarkable inhibition on UGT1A8, with IC50 values of 6.89±0.812μM and 5.85±0.821μM, respectively. Although the inhibitory effect was low, both 20(R)-PPT and 20(S)-PPT also inhibited UGT1A8 activity. Considering 1) that the relative contents of 20(R)-Rg3 in processed ginseng are high, 2) that higher exposure to (R)-isomers of ginsenosides occur in the intestine compared to that in the liver, and 3) the inhibitory effects of other ginsenosides on enzymatic activity [20(S)-Rg3, 20(S)-Rh2, 20(R)- and 20(S)-PPT], there may be a potential for herb-drug interactions between processed ginseng and UGT1A8 substrates when concomitantly administered.
我们在体外评估了六对人参皂苷异构体（20位手性碳上的立体异构体）抑制几种UDP-葡萄糖醛酸基转移酶（UGT）同工酶酶活性的潜力，这些同工酶是人类II相药物代谢的主要参与者。结果表明，所测试的六对人参皂苷异构体对所研究的十种UGT同工酶表现出不同程度的立体选择性抑制作用。在所测试的十二种具有立体选择性的人参皂苷中，20(R)-Rg3对UGT1A8同工型的抑制作用最强，最低IC50值为5.66±1.04μM。另一方面，Rg3和Rh2的(S)-异构体对UGT1A8也有显著抑制作用，IC50值分别为6.89±0.812μM和5.85±0.821μM。虽然抑制作用较弱，但20(R)-PPT和20(S)-PPT也抑制UGT1A8活性。考虑到1）炮制人参中20(R)-Rg3的相对含量较高，2）与人参皂苷(R)-异构体在肝脏中的暴露量相比，在肠道中的暴露量更高，以及3）其他人参皂苷（20(S)-Rg3、20(S)-Rh2、20(R)-和20(S)-PPT）对酶活性的抑制作用，当同时给药时，炮制人参和UGT1A8底物之间可能存在药物相互作用的潜在风险。
