School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China.
School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China.
Drug Metab Rev. 2020 May;52(2):235-257. doi: 10.1080/03602532.2020.1758714. Epub 2020 May 14.
Due to the rapidly increasing global interest in the use of herbs, phytomedicines and other natural products as medical or complementary remedies, concerns about the clinical medication safety have drawn much attention worldwide. Particularly, many natural ingredients exhibit inhibitory effects on cytochrome P450 (CYP) enzymes, which are the most important Phase I metabolism enzymes in liver. CYP2C9 is one of the most abundant CYP enzymes and responsible for the metabolism of over 15% clinical drugs, including oral sulfonylurea hypoglycemics, nonsteroidal anti-inflammatory agents, selective cyclooxygenase-2 inhibitors, antiepileptics, angiotensin II receptor inhibitors and anticoagulants. Diclofenac (4'-hydroxylase) and tolbutamide (methylhydroxylation) are widely used as probe substrates for CYP2C9. To date, numerous natural products have been reported to have the capabilities of inhibiting the catalytic activity of CYP2C9 and further influencing the pharmacokinetic and pharmacodynamic behaviors of drugs that are mainly metabolized by CYP2C9, leading to potential herb-drug interactions. Moreover, some fatal adverse interactions may occur for drugs with a narrow therapeutic window when they are coadministered with a CYP2C9 inhibitor, especially irreversible inactivators. For the purpose of better understanding the interactions of natural products with CYP2C9, we comprehensively reviewed the characteristics of CYP2C9, the natural ingredients that inhibit CYP2C9, the related research approaches and strategies, the types of inhibition and the underlying mechanisms.
由于全球对草药、植物药和其他天然产品作为医疗或补充疗法的兴趣迅速增加，对临床用药安全性的关注已引起全球关注。特别是许多天然成分对细胞色素 P450（CYP）酶具有抑制作用，CYP 酶是肝脏中最重要的 I 相代谢酶。CYP2C9 是最丰富的 CYP 酶之一，负责代谢超过 15%的临床药物，包括口服磺酰脲类降糖药、非甾体抗炎药、选择性环氧化酶-2 抑制剂、抗癫痫药、血管紧张素 II 受体抑制剂和抗凝剂。双氯芬酸（4'-羟化酶）和甲苯磺丁脲（甲基羟化酶）被广泛用作 CYP2C9 的探针底物。迄今为止，已有大量天然产物被报道具有抑制 CYP2C9 催化活性的能力，并进一步影响主要由 CYP2C9 代谢的药物的药代动力学和药效学行为，导致潜在的草药-药物相互作用。此外，当与 CYP2C9 抑制剂联合使用时，一些治疗窗较窄的药物可能会发生致命的不良反应相互作用，尤其是不可逆失活剂。为了更好地了解天然产物与 CYP2C9 的相互作用，我们全面回顾了 CYP2C9 的特性、抑制 CYP2C9 的天然成分、相关研究方法和策略、抑制类型和潜在机制。
