Protective effects of goldenseal (Hydrastis canadensis L.) on acetaminophen-induced hepatotoxicity through inhibition of CYP2E1 in rats.
BACKGROUND
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.


METHODS
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.


RESULTS
Goldenseal extract inhibited CYP1A2, CYP2D6, CYP2E1, and CYP3A activity, and the inhibitory effect on CYP2E1 was the strongest (IC(50) 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.


CONCLUSIONS
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.
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan.
Katsunori
K
Yamaura
Maki
M
Shimada
Noriyuki
N
Nakayama
Koichi
K
Ueno