体外代谢体系中中药及其成分对肝脏CYP450代谢酶抑制作用的研究进展

引用本文

ZHANG Wen-wen, LIU Xin, WEN Cheng-ming, JIANG Xue-hua, WANG Ling. Review of the in vitro inhibitory effects of traditional Chinese medicine and its components on CYP450 enzymes in liver microsomes[J]. Acta Pharmaceutica Sinica, 2022, 57(2): 303-312.

张雯雯, 刘鑫, 温成铭, 蒋学华, 王凌. 体外代谢体系中中药及其成分对肝脏CYP450代谢酶抑制作用的研究进展[J]. 药学学报, 2022, 57(2): 303-312.

体外代谢体系中中药及其成分对肝脏CYP450代谢酶抑制作用的研究进展

张雯雯¹, 刘鑫², 温成铭¹, 蒋学华¹, 王凌¹

1. 四川大学华西药学院临床药学与药事管理学系, 四川成都 610041;
2. 中南大学湘雅医院临床药理研究所, 湖南长沙 410000

收稿日期: 2021-09-18; 修回日期: 2021-11-03

^*通讯作者: 王凌, E-mail: wlin_scu@scu.edu.cn

摘要: 细胞色素P450（CYP450）是肝微粒体中参与体内I相代谢反应的酶，临床上90%以上的药物都经CYP450氧化代谢，其被诱导或抑制是引起药物相互作用的主要机制。通过离体器官、细胞或酶系统进行的体外代谢研究以其精准、简化等特点近年来发展迅速。中药的体外代谢研究可推断药物可能的代谢途径和参与代谢的CYP450酶，研究药物的相互作用，更好地解释中药及其成分的作用机制，促进临床合理用药。本文就中药、中药成分、中药提取物在不同种属肝微粒体中对CYP450代谢酶活性的抑制作用进行综述，以期为中药-中药、中药-化学药物之间相互作用研究提供借鉴与参考。

关键词: 细胞色素P450 中药体外代谢肝微粒体药物相互作用

Review of the in vitro inhibitory effects of traditional Chinese medicine and its components on CYP450 enzymes in liver microsomes

ZHANG Wen-wen¹, LIU Xin², WEN Cheng-ming¹, JIANG Xue-hua¹, WANG Ling¹

1. Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu 610041, China;
2. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410000, China

Abstract: Cytochrome P450s (CYP450) is a superfamily of phase I metabolic enzymes, which participates in more than 90% of drug oxidation. The induction or inhibition of CYP450s is the main mechanism of drug-drug interaction. In recent years, in vitro metabolism studies conducted through isolated organs, cells, or enzyme systems have developed rapidly, due to their precision and simplicity. Therefore, profiles of the in vitro metabolism studies of traditional Chinese medicines can infer the possible metabolic pathways of drugs, predict the potential drug interactions, and may enhance the rational use of drugs in clinic. This article reviews the in vitro inhibitory effects of traditional Chinese medicine, ingredients, and extracts on the activities of CYP450 enzymes in the liver microsomes, which can provide a reference for further researches on the interaction between Chinese medicine and chemical medicine.

Key words: cytochrome P450 traditional Chinese medicine in vitro metabolism liver microsome drug-drug interaction

细胞色素P450 (CYP450) 是指含血红素的蛋白质在一氧化碳存在的还原性状态下, 最大吸收波长在450 nm的一类能够催化大多数药物和其他亲脂性外源性物质的主要代谢酶家族。CYP450代谢酶在体内广泛分布, 以肝脏、小肠含量最高。人类CYP450代谢酶分为18个家族和44个亚家族, 其中CYP1/2/3家族中的代谢酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1和CYP3A4) 参与临床上90%以上药物的I相代谢过程, 其他家族在代谢内源性物质方面发挥重要的作用^{[1, 2]}。CYP450代谢酶的表达和活性受多种因素影响, 如年龄、性别、遗传、环境及病理因素等, 其活性被抑制可导致经其代谢的药物在体内代谢减慢, 暴露量增加, 从而增大不良反应发生概率, 对于前药而言则会导致药物疗效减弱。CYP450代谢酶具有泛底物性和底物交叉性, 底物与活性中心非特异性结合会导致药物的代谢动力学发生改变, 从而引起药物-药物之间相互作用^[3]。

随着中西医结合治疗的发展, 中药方剂及中成药与化学药品联合使用不断增多, 中药-化学药物之间的相互作用及不良反应数量也逐渐上涨。中药成分按照其母核结构可分为生物碱类、黄酮类、萜类、苷类等。目前中药对CYP450代谢酶影响的研究方法主要有探针药物法、体外孵育法(肝微粒体及重组P450酶)、计算机软件模拟筛选法^{[4, 5]}。探针药物法是指通过底物的特定氧化代谢途径来确定体内外特异性代谢酶活性的一种CYP酶-底物配对的检测方法, 分为体内探针药物法及体外探针药物法^[6], 体内探针药物法是指给予机体一定量的探针药物后以其代谢物和原形药物之间的比例或速率来衡量代谢酶活性的变化, 在研究代谢酶与疾病之间的关系及药物之间在机体内的相互作用具有更高的价值。

由于体内研究影响因素颇多, 中药代谢及其机制研究受限。体外模型, 尤其是以肝微粒体为核心的药物代谢模型具有专属性强、灵敏度高等特点^[7], 在提高药物疗效、促进安全合理用药等方面具有重要意义。本文就目前以肝微粒体为体外代谢模型, 开展中药及其成分对主要CYP450代谢酶的抑制作用进行综述。

1 CYP1A2

CYP1家族由CYP1A1、1A2、1B1组成, 其中CYP1A2约占总P450的13%~15%^[8], 参与代谢临床上大多数药物如咖啡因、非那西丁、氯氮平、茶碱、普萘洛尔、维拉帕米、哌唑嗪、杜洛西汀等^[9]。其中非那西丁、咖啡因和茶碱常作为模型底物评价CYP1A2代谢酶的体内活性。在超过45%的新药体外研究中, 非那西丁-O-去甲基化反应作为检测CYP1A2活性最常用的探针反应^[10]。部分中药及其成分对CYP1A2抑制作用见表 1^[11-26]。

Table 1 Inhibition of traditional Chinese medicine and its components on CYP1A2. HLM: Human liver microsome; RLM: Rat liver microsome; -: Not obtained

根据《FDA药物相互作用研究指南》体内相互作用的可能性通过R = [I] / K_i ([I] 代表作用部位抑制剂的浓度, K_i为抑制剂常数) 表示, R > 1表明很有可能发生药物间的相互作用。当由体外数据定量预测体内相互作用发生的可能性时, 可以通过K_i值进行初步筛选, 数值越小, 外推至体内发生相互作用的可能性越大。测定半数抑制浓度(IC₅₀) 值可快速初步了解药物对代谢酶是否具有强抑制作用, IC₅₀值越小说明抑制作用越强。若IC₅₀ < 1.00 μmol·L^-1, 初步表明药物对该代谢酶的抑制能力强; 若IC₅₀ > 50 μmol·L^-1则表明药物对该代谢酶抑制作用较弱, 外推至体内时由于药物抑制该代谢酶的活性而引起的药物相互作用可能性较小^[27]。在所列举的中药及其成分中, 对CYP1A2代谢酶的活性抑制作用较强的分别是丹红注射液(IC₅₀ = 0.036 μmol·L^-1), 大叶茜草素(IC₅₀ = 1.03 μmol·L^-1) 和甘草酚(IC₅₀ = 2.2 μmol·L^-1)。

2 CYP2C

CYP2C家族占人类肝脏总P450的30%左右, 主要包括CYP2C8、2C9、2C19, 能代谢20%以上的药物和内源性化合物^[28]。CYP2C8约占肝脏总P450的7%, 底物主要包括抗肿瘤药物(紫杉醇)、降糖药物(瑞格列奈和吡格列酮)、降脂药物(氟伐他汀)、抗疟药物(阿莫地喹) 等60多种临床常用药物, 常用紫杉醇-6-羟基化检测CYP2C8代谢酶的活性^[29]。CYP2C9占肝脏总P450的20%左右, 临床上15%的药物经其代谢, 底物主要有糖尿病治疗药物(格列美脲)、降压药(氯沙坦)、抗癫痫药物、非甾类抗炎药物(双氯芬酸)^[30], 双氯芬酸-4-羟基化用于检测CYP2C9活性^[29]。虽然CYP2C19在肝脏的表达仅占肝脏总P450代谢酶的1%, 但能参与临床上10%左右的药物代谢。代谢底物主要包括质子泵抑制剂(奥美拉唑、泮托拉唑等)、抗抑郁药(舍曲林、氟西汀)、镇静催眠药(地西泮、苯巴比妥)、抗血小板药物(氯吡格雷)^[31], 美酚妥英-4-羟基化常作为探针反应用于检测CYP2C19代谢酶活性。部分中药及其成分对CYP2C抑制作用见表 2^{[12, 15, 18, 24, 25, 32-55]}。

Table 2 Inhibition of traditional Chinese medicine and its components on CYP2C. HRC: Human recombinant CYP

Category	Name	Source	CYP2C	In vitro model	IC₅₀	Inhibition type	Ref.
Alkaloid	Epiberberine	Rhizoma Coptidis	CYP2C9	HLM	8.18 μmol·L^-1	Anti-competitive	[32]
	Phellodendrine	Phellodendri	CYP2C9	HLM	16.30 μmol·L^-1	Competitive	[33]
	Sophocarpine	Sophora	CYP2C9	HLM	15.96 μmol·L^-1	Competitive	[34]
Flavone	Kaempferitrin	Vepris heterophylla	CYP2C9	HLM	16.42 μmol·L^-1	Competitive	[12]
	Cynaroside	Angelica keiskei	CYP2C9	HLM	16.58 μmol·L^-1	Competitive	[35]
Terpenoid	Pachymic acid	Poria	CYP2C9	HLM	27.95 μmol·L^-1	Competitive	[36]
	Alantolactone	Helenium	CYP2C9	HLM	36.82 μmol·L^-1	-	[37]
	Dihydrotanshinone	Salvia miltiorrhiza	CYP2C19	HLM	0.1 μmol·L^-1	Mixed	[38]
	Miltirone	Salvia miltiorrhiza	CYP2C9	HLM	8.61 μmol·L^-1	Competitive	[39]
	Celastrol	Tripterygium wilfordii	CYP2C11	RLM	10.2 μmol·L^-1	Competitive	[40]
The other compound	Osthole	Angelica	CYP2C9	HLM	5.736 μg·mL^-1	Competitive	[41]
			CYP2C11	RLM	11.33 μg·mL^-1	Non-competitive
	Honokiol	Magnolia officinalis	CYP2C11	RLM	16.5 μmol·L^-1	Mixed	[15]
	Rosmarinic acid	Rosemary	CYP2C9	HRC	39.6 μmol·L^-1	Mixed	[42]
			CYP2C9	HLM	76.89 μmol·L^-1	-	[43]
	Sauchinone	Saururus chinensis	CYP2C19	HLM	3.60 μmol·L^-1	Non-competitive	[44]
	Shikonin	Boraginaceae	CYP2C9	HLM	1.01 μmol·L^-1	Mixed	[45]
			CYP2C11	RLM	2.36 μmol·L^-1	Mixed
	Bergenin	Bergenia purpurascens	CYP2C9	HLM	15.11 μmol·L^-1	Competitive	[46]
	Glycyrol	Glycyrrhiza uralensis	CYP2C9	HLM	0.13 μmol·L^-1	Competitive	[18]
	Cajaninstilbene acid	Pigeonpea	CYP2C9	HLM	31.3 μmol·L^-1	Competitive	[47]
	Curculigoside	Curculigo	CYP2C8	HLM	11.93 μmol·L^-1	Competitive	[48]
	Catalpol	Rehmanniae Radix	CYP2C9	HLM	14.69 μmol·L^-1	Competitive	[49]
Traditional Chinese medicine extract	Tinospora cordifolia extracts	-	CYP2C9	HLM	127.55 μg·mL^-1	-	[50]
	Ethanol extract of Descurainia sophia seeds	Descurainia sophia	CYP2C9	HLM	25.8 ± 1.9 μg·mL^-1	Mixed	[51]
			CYP2C19	HLM	38.7 ± 1.7 μg·mL^-1	Mixed
	Danshen ethanolic extract	Salvia miltiorrhiza Bunge	CYP2C19	HLM	30.9 μg·mL^-1	Competitive	[38]
	Marsdenia tenacissima extract	Marsdenia tenacissima	CYP2C9	HLM	12.68 mg·mL^-1	-	[52]
			CYP2C19	HLM	25.48 mg·mL^-1	-
	Sophora flavescens extract	Sophora favescens	CYP2C8	HLM	1.42 μg·mL^-1	-	[53]
			CYP2C9	HLM	13.6 μg·mL^-1	Competitive
			CYP2C19	HLM	19.1 μg·mL^-1	-
	Labisia pumila extracts	Labisa pumila	CYP2C8	HLM	2.39 μg·mL^-1	Non-competitive	[54]
			CYP2C9	HLM	0.56 μg·mL^-1	Competitive
			CYP2C19	HLM	4.1 μg·mL^-1	Non-competitive
Chinese patent medicine	Qingfei Paidu decoction	-	CYP2C8	HLM	337.7 ± 43.3 μg·mL^-1	-	[24]
		-	CYP2C9	HLM	706.8 ± 71.1 μg·mL^-1	-
	Bovis Calculus Artifactus	Bovis Calculus	CYP2C11	RLM	3.71 μmol·L^-1	-	[55]
	Huosu Yangwei oral liquid	-	CYP2C8	HLM	1.191 mg·mL^-1	-	[25]
		-	CYP2C9	HLM	1.815 mg·mL^-1	-
		-	CYP2C19	HLM	1.272 mg·mL^-1	-

Table 2 Inhibition of traditional Chinese medicine and its components on CYP2C. HRC: Human recombinant CYP

对CYP2C9抑制作用最强的中药成分是甘草酚(IC₅₀ = 0.13 μmol·L^-1), 对CYP2C19抑制作用最强的中药成分是黄酮类的二氢丹参酮(IC₅₀ = 0.1 μmol·L^-1)。二氢丹参酮是丹参中主要的醌类脂溶性化合物之一, 体外抗肿瘤活性明显, 可通过抑制细胞增殖、促进细胞凋亡、诱导细胞分化等机制发挥抗肿瘤作用^[56]。目前二氢丹参酮尚未作为单一成分成药, 已经上市的中药注射剂丹参注射液中二氢丹参酮含量较低, 故目前由于二氢丹参酮抑制体内CYP2C19代谢酶活性而引起的药物相互作用的可能性较小。随着二氢丹参酮在抗肿瘤方面的研究不断进展, 其单独成药的可能性也不断增大, 对于其在体内对CYP2C19代谢酶活性的抑制作用而引起的药物相互作用也不容忽视。

迷迭香酸在不同的体外模型中对CYP2C9抑制程度也不同, 在人肝微粒体(HLM) 中IC₅₀ = 76.89 μmol·L^-1, 在基因重组酶系(HRC) 中IC₅₀ = 39.6 μmol·L^-1。基因重组酶系与人体内相同酶的丰度差异较大, 只能用来对药物代谢进行细节化的研究, 其实验得到的结果不能外推到人体代谢。因此, 在HRC中迷迭香酸对CYP2C9抑制作用更明显, IC₅₀值相比于HLM也更小, 显示出更强的抑制作用。

3 CYP2D6

CYP2D6仅占肝脏总P450含量的2%~4%, 但能参与25%左右的临床常用药物的代谢^[57], 其代谢底物主要包括抗抑郁药(氟西汀、丙咪嗪、度洛西汀等)、抗心律失常药物(普罗帕酮、美西律、利多卡因等)、抗高血压药物如β受体阻断剂(普萘洛尔)、抗组胺药物(氯雷他定、异丙嗪、特非那定)、抗病毒药物(茚地那韦)^[58], 常用右美沙芬-O-去甲基化作为检测CYP2D6代谢酶活性的探针反应^[59]。部分中药及其成分对CYP2D6抑制作用见表 3^{[24, 25, 32, 43, 45, 60-65]}。

Table 3 Inhibition of traditional Chinese medicine and its components on CYP2D6

丹红注射液对CYP2D6代谢酶活性的抑制作用最强(IC₅₀ = 0.144 μmol·L^-1)。丹红注射液由丹参和红花两味中药组成, 主要功效为活血化瘀、舒脉通络, 临床广泛用于治疗冠心病、心绞痛、心肌梗死、脑血栓等心脑血管疾病, 常与阿司匹林、氯吡格雷、阿托伐他汀钙注射液等合用^[66]。由于CYP2D6参与代谢的底物涉及大多数心血管系统药物如β受体阻断剂等, 故在联合使用丹红注射液治疗急性心肌梗死、冠心病、充血性心力衰竭时应注意中药所引起的药物相互作用, 谨慎使用。

4 CYP2E1

CYP2E1占肝脏中CYP450总量的7%, 能代谢大多数内源性小分子化合物和药物, 代谢底物主要包括对乙酰氨基酚、氯唑沙宗、苯、四氯化碳等^[67]。常用氯唑沙宗-6-羟基化作为检测CYP2E1代谢酶活性的探针反应。部分中药及其成分对CYP2E1抑制作用见表 4^{[13, 14, 25, 26, 36, 43, 46, 49, 62, 63, 68-74]}。

Table 4 Inhibition of traditional Chinese medicine and its components on CYP2E1

CYP2E1可活化肝毒性物质及前致癌物质, 参与多种疾病的发生。所列举的中药及其成分中金合欢素(IC₅₀ = 12.36 μmol·L^-1) 对CYP2E1代谢酶抑制作用较强。金合欢素是一种天然黄酮类化合物, 具有抗炎、抗氧化、抗肿瘤等广泛的药理活性^[75]。研究表明, 金合欢素可以有效地抑制CYP1B1代谢酶的活性, 阻止雌激素致癌代谢产物的生成, 从而预防肿瘤的发生^[76]。随着对金合欢素生物活性及作用机制的不断探索, 其能否通过抑制CYP2E1活性, 减少致癌代谢物质的生成, 从而预防肿瘤的发生, 成为一种有效的抗肿瘤药物, 还需要进一步的实验验证。

IC₅₀值取决于代谢体系中底物浓度及酶浓度等因素, 例如丹红注射液在所汇总的两篇文献中IC₅₀值分别为0.197%^[26] (底物氯唑沙宗浓度为40 μmol·L^-1, 肝微粒体浓度为0.25 mg·mL^-1) 和1.10%^[43] (氯唑沙宗浓度为50 μmol·L^-1, 肝微粒体浓度为0.3 mg·mL^-1), 因此在比较同一化合物对同一代谢酶在不同实验室的抑制结果时应保持实验条件一致。

5 CYP3A

CYP3A是广泛分布于机体各个组织, 主要包括CYP3A4、3A5、3A7、3A43四个亚家族, 是人类肝脏和小肠中CYP450含量最多的一个家族, 其中CYP3A4约占肝脏总P450含量的50%左右, 小肠中大约含有40% CYP3A4^[77], 迄今为止, 已有超过50%的治疗药物被CYP3A4代谢, 如钙通道阻滞剂(硝苯地平)、抗肿瘤药物(多烯紫杉醇、环磷酰胺、他莫昔芬) 等^[78], 咪达唑仑是一种短效苯二氮䓬类镇静催眠药物, 经CYP3A代谢酶催化生成1-OH咪达唑仑, 是测定体内外CYP3A最常用的探针底物之一^[79]。部分中药及其成分对CYP3A的抑制作用见表 5^{[12, 14, 16, 32-37, 40, 44, 46-49, 52, 55, 60, 62-64, 71, 80-99]}。

Table 5 Inhibition of traditional Chinese medicine and its components on CYP3A

Category	Name	Source	CYP3A	In vitro model	IC₅₀	Inhibition type	Ref.
Alkaloid	Cornin	Verbena officinalis	CYP3A4	HLM	9.20 μmol·L^-1	Non-competitive	[80]
	Epiberberine	Rhizoma Coptidis	CYP3A4	HLM	81.5 μmol·L^-1	-	[32]
	Peimine	Fritillaria ussuriensis	CYP3A4	HLM	13.43 μmol·L^-1	Non-competitive	[60]
	Phellodendrine	Phellodendri chinensis cortex	CYP3A4	HLM	14.98 μmol·L^-1	Non-competitive	[33]
	Sophocarpine	Sophora	CYP3A4	HLM	12.22 μmol·L^-1	Non-competitive	[34]
	Brucine	Strychnos nuxvomica L.	CYP3A4	HLM	0.77 μmol·L^-1	Competitive	[81]
Flavone	Astilbin	Smilacis glabrae Roxb	CYP3A4	HLM	2.63 μmol·L^-1	Non-competitive	[82]
	lysionotin	Lysionotus	CYP3A4	HLM	13.85 μmol·L^-1	Non-competitive	[83]
	Kaempferitrin	Justicia spicigera	CYP3A4	HLM	13.87 μmol·L^-1	Non-competitive	[12]
	Cynaroside	Angelica keiskei	CYP3A4	HLM	15.88 μmol·L^-1	Non-competitive	[35]
	Dihydromyricetin	Ampelopsis grossedentata	CYP3A4	HLM	14.75 μmol·L^-1	Non-competitive	[62]
	Licochalcone A	liquorice	CYP3A4	HLM	2.77 μmol·L^-1	Competitive	[84]
	Puerarin	Puerariae Radix	CYP3A4	HLM	15.5 ± 3.9 μmol·L^-1	-	[85]
	Acacetin	Lygodium japonicum	CYP3A1	RLM	58.46 μmol·L^-1	Mixed	[86]
	Apigenin	Lygodium root	CYP3A1	RLM	8.20 μmol·L^-1	-
	Chrysin	Propolis	CYP3A4	HLM	2.5 ± 0.6 μmol·L^-1	-	[87]
	Myricetin	Myricaceae	CYP3A4	HLM	20.29 μmol·L^-1	Non-competitive	[88]
			CYP3A2	RLM	27.14 μmol·L^-1	Mixed
	Isobavachalcone	Fructus Psoraleae	CYP3A4	HLM	35.20 μmol·L^-1	Competitive	[89]
	Methylophiop-ogonanone A	Ophiopogon japonicas	CYP3A	HLM	2.75 μmol·L^-1	-	[90]
Terpenoid	Ganoderic acid A	Ganoderma lucidum	CYP3A4	HLM	15.05 μmol·L^-1	Non-competitive	[63]
	Catalpol	Rehmanniae Radix	CYP3A4	HLM	14.27 μmol·L^-1	Non-competitive	[49]
	Friedelin	Maytenus ilicifolia	CYP3A4	HLM	10.79 μmol·L^-1	Non-competitive	[71]
	Glycyrrhetinic acid	Licorice	CYP3A4	HLM	1.53 μmol·L^-1	-	[91]
	Alantolactone	Helenium	CYP3A4	HLM	3.599 μmol·L^-1	Non-competitive	[37]
	Celastro	Trypterygium wilfordi Hook	CYP3A2	RLM	23.2 μmol·L^-1	Mixed	[40]
	Dihydrotanshinone	Danshen	CYP3A2	RLM	56.1 μmol·L^-1	-	[92]
Phenol	Curculigoside	Curculigo orchioides	CYP3A4	HLM	9.47 μmol·L^-1	Competitive	[48]
The other compound	Anemarsaponin BII	Anemarrhena asphodeloides	CYP3A4	HLM	13.67 μmol·L^-1	Non-competitive	[64]
	Pachymic acid	Poria	CYP3A4	HLM	15.04 μmol·L^-1	Non-competitive	[36]
	Isofraxidin	Umbelliferae	CYP3A4	HLM	15.49 μmol·L^-1	Non-competitive	[14]
	Sauchinone	Saururaceae	CYP3A4	HLM	0.207 μmol·L^-1	Non-competitive	[44]
	Bergenin	Bergenia purpurascens	CYP3A4	HLM	14.39 μmol·L^-1	Non-competitive	[46]
	Sodium tanshinone IIA sulfonate	Danshen	CYP3A4	HLM	6.4 μmol·L^-1	Competitive	[93]
	Cajaninstilbene acid	Pigeonpea	CYP3A4	HLM	28.3 μmol·L^-1	-	[47]
	Gomisin B	Schisandra chinensis	CYP3A4	HLM	0.76 μmol·L^-1	-	[94]
	Gomisin C		CYP3A4	HLM	0.059 ± 0.03 μmol·L^-1	-	[95]
	Magnolol	Magnolia officinalis	CYP3A	RLM	35.0μmol·L^-1	Competitive	[16]
Traditional Chinese medicine extract	Huang-Lian-Jie-Du- decoction-total flavonoids	-	CYP3A1	RLM	4.24 μg·mL^-1	-	[96]
	Huang-Lian-Jie-Du- decoction-total alkaloids	-	CYP3A1	RLM	2.61 μg·mL^-1	-
	Marsdenia tenacissima extract	Marsdenia tenacissima	CYP3A4	HLM	11.25 mg·mL^-1	-	[52]
	Danshen extract	Salvia miltiorrhiza Bunge	CYP3A4	HLM	136 μg·mL^-1	Competitive	[97]
			CYP3A1	RLM	748 μg·mL^-1	Competitive
Chinese patent medicine	Bovis Calculus Artifactus	Bovis Calculus	CYP3A1	RLM	0.17 μmol·L^-1	-	[55]
	Dengzhan Shengmai capsule	-	CYP3A1	RLM	0.02 mg·mL^-1	-	[98]
	Salvianolate	-	CYP3A4	HLM	1.438 mg·L^-1	Non-competitive	[99]

Table 5 Inhibition of traditional Chinese medicine and its components on CYP3A

生物碱类中对CYP3A代谢酶活性抑制作用最强的是马钱子碱(IC₅₀ = 0.77 μmol·L^-1), 马钱子碱是传统中药马钱子的主要有效成分, 其含量占马钱子总生物碱的30%~40%, 具有显著的镇痛、抗炎、抗肿瘤作用^[100]。目前国内外有关报道已经能从细胞水平、分子水平等方面解释其作用机制, 有关马钱子碱的研究趋势是如何将其开发成安全、有效的药用新剂型, 充分发挥其药理作用。在将其开发成新剂型时的临床前药物研究, 应充分考虑其对CYP3A4代谢酶活性的抑制作用。

木脂素类中五味子乙素和五味子丙素对CYP3A4抑制作用最强, IC₅₀值分别为0.76 μmol·L^-1和0.059 ± 0.03 μmol·L^-1。五味子为木兰科植物五味子的干燥成熟果实, 主要含有木脂素、挥发油类、黄酮类、萜类等活性成分, 药理研究表明具有保护肝脏、镇静催眠、降血糖、抗氧化及增强免疫力抗肿瘤等作用, 木脂素为五味子中主要的特征性活性成分, 约占8%^[101]。研究表明, 五味子乙素连续3天灌胃给药后, 大鼠体内CYP3A4探针底物咪达唑仑药动学发生显著变化, 咪达唑仑的血药浓度-时间曲线下面积(AUC) 增大约60%, 咪达唑仑经CYP3A4代谢产物羟基咪达唑仑的AUC降低^[102]。目前有五味子胶囊、参芪五味子片等由五味子做成的著名中成药, 有健脾安神、益气宁心等功效, 常用于一些疾病的辅助治疗, 故在与经CYP3A4代谢的药物合用时应注意由中药所引起的药物相互作用。

6 结语

近年来, 中西医联合治疗已经成为治疗疾病的常用方法, 尤其对于一些慢性疾病如高血压、糖尿病等在化学药物治疗的同时经常合用一些中成药。中药或其成分对肝脏中CYP450代谢酶活性产生抑制作用会直接影响该代谢酶底物的药动学过程, 从而对其药效产生影响。由于体内实验受干扰因素较多, 无法完全阐明由中药引起的不良反应机制及代谢机制, 限制了其在探究中药及其成分与CYP450代谢酶之间相互作用方面的应用。肝微粒体的体外代谢研究对于明确中药及其成分的代谢途径、阐明中药配伍使用达到增效减毒的代谢机制、探究中药或其成分对肝微粒体中相关代谢酶的影响, 以阐明其不良反应的机制有着积极的作用。

同时对于中药代谢探究仍有不足, 如未能从蛋白结构与分子结构层面上解释其抑制原理等。因此, 还需发展相应技术和研究方法, 结合体内实验深入探究中药的物质组成和结果特征并在此基础上阐明其作用机制, 减少由中药与CYP450代谢酶相互作用引起的药物不良反应, 从而促进中医药的现代化发展。

作者贡献: 张雯雯负责文献检索及论文撰写; 刘鑫负责文献检索及修改文章; 温成铭负责修改文章; 蒋学华负责审阅文章; 王凌负责文章选题、指导写作、修改及校对文章。

利益冲突: 本文无任何利益冲突问题。

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药学学报 2022, Vol. 57 Issue (2): 303-312 DOI: 10.16438/j.0513-4870.2021-1384	PDF