Protective effects of goldenseal (Hydrastis canadensis L.) on acetaminophen-induced hepatotoxicity through inhibition of CYP2E1 in rats.
Protective effects of goldenseal (Hydrastis canadensis L.) on acetaminophen-induced hepatotoxicity through inhibition of CYP2E1 in rats.
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DOI：
10.4103/0974-8490.89745
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发表时间：
2011-10
影响因子：
0.7
通讯作者：
Ueno K
中科院分区：
文献类型：
--
作者：
Yamaura K;Shimada M;Nakayama N;Ueno K
北美毛茛在体外抑制多种细胞色素P450（CYP）亚型，如CYP 2C 9、CYP 2C 19、CYP 2D 6、CYP 2 E1和CYP 3A。高剂量的对乙酰氨基酚（APAP）产生高活性中间体N-乙酰基-对苯醌亚胺（NAPQI），主要由CYP 2 E1催化。本研究的目的是探讨口服毛茛通过抑制CYP 2 E1对APAP诱导的急性肝衰竭（ALF）的保护作用。雄性Wistar大鼠在口服APAP（400 mg/kg）前2、18和26 h以及口服APAP（400 mg/kg）后6 h经口给予goldenseal（300和1000 mg/kg）。检测血清谷草转氨酶（AST）和丙氨酸转氨酶（ALT）活性以及血清APAP浓度。黄精提取物对CYP 1A 2、CYP 2D 6、CYP 2 E1和CYP 3A均有抑制作用，其中对CYP 2 E1的抑制作用最强（IC 50为4.32 μg/mL）。黄连（300 mg/kg）可显著抑制APAP引起的血清AST和ALT升高，且黄连的保肝作用强于水飞蓟素（200 mg/kg）。此外，血清中APAP浓度增加，毛茛治疗，推测是由于毛茛抑制作用的APAP代谢为NAPQI。这些结果表明，毛茛改善APAP诱导的ALF，这种保护作用可能归因于抑制CYP 2 E1活性，该活性产生APAP的高反应性中间体。
Goldenseal (Hydrastis canadensis L.) inhibits various cytochrome P450 (CYP) isoforms such as CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A in vitro. High doses of acetaminophen (APAP) generate the highly reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), catalyzed mainly by CYP2E1. The aim of this study was to investigate the hepatoprotective effects of orally administrated goldenseal against APAP-induced acute liver failure (ALF) via inhibition of CYP2E1. Male Wistar rats were treated orally with goldenseal (300 and 1000 mg/kg) 2, 18, and 26 h before and 6 h after oral APAP (400 mg/kg) administration. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as serum APAP concentration were evaluated. Goldenseal extract inhibited CYP1A2, CYP2D6, CYP2E1, and CYP3A activity, and the inhibitory effect on CYP2E1 was the strongest (IC50 4.32 μg/mL). Treatment with goldenseal (300 mg/kg) significantly attenuated the APAP-induced increase in serum AST and ALT, and the hepatoprotective effect of goldenseal was stronger than that of silymarin (200 mg/kg). Moreover, serum APAP concentration was increased by goldenseal treatment, presumably as a result of the inhibitory effect of goldenseal on the metabolism of APAP to NAPQI. These results suggest that goldenseal ameliorates APAP-induced ALF and that this protection can likely be attributed to the inhibition of CYP2E1 activity, which generates the highly reactive intermediate of APAP.