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.

中文翻译：

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天然产物对CYP2C9的抑制作用：深入了解草药与药物相互作用的潜在风险。

由于全球对使用草药，植物药和其他天然产品作为医学或补充药物的兴趣迅速增长，对临床药物安全性的关注已引起全世界的广泛关注。特别是，许多天然成分对细胞色素P450（CYP）酶具有抑制作用，CYP是肝脏中最重要的I期代谢酶。CYP2C9是最丰富的CYP酶之一，负责15％以上的临床药物的代谢，包括口服磺酰脲类降糖药，非甾体抗炎药，选择性环氧合酶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）和甲苯磺丁酰胺（甲基羟化）被广泛用作CYP2C9的探针底物。至今，据报道，许多天然产物具有抑制CYP2C9的催化活性并进一步影响主要由CYP2C9代谢的药物的药代动力学和药效动力学行为的能力，从而导致潜在的草药相互作用。此外，与CYP2C9抑制剂（尤其是不可逆的灭活剂）共同给药时，如果治疗窗口狭窄，可能会发生致命的不良相互作用。为了更好地理解天然产物与CYP2C9的相互作用，我们全面综述了CYP2C9的特性，抑制CYP2C9的天然成分，相关的研究方法和策略，抑制的类型及其潜在机理。