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. 2019 Aug 10;11(8):1862.
doi: 10.3390/nu11081862.

Epigallocatechin-3-Gallate Reduces Hepatic Oxidative Stress and Lowers CYP-Mediated Bioactivation and Toxicity of Acetaminophen in Rats

Hsien-Tsung Yao  1 , Chien-Chun Li  2 , Chen-Hui Chang  3
Affiliations

Epigallocatechin-3-Gallate Reduces Hepatic Oxidative Stress and Lowers CYP-Mediated Bioactivation and Toxicity of Acetaminophen in Rats

Hsien-Tsung Yao et al. Nutrients. .

Abstract

Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea. To investigate the effects of dietary EGCG on oxidative stress and the metabolism and toxicity of acetaminophen in the liver, rats were fed diets with (0.54%) or without EGCG supplementation for four weeks and were then injected intraperitoneally with acetaminophen (1 g/kg). The results showed that EGCG lowered hepatic oxidative stress and cytochrome P450 (CYP) 1A2, 2E1, and 3A, and UDP-glucurosyltransferase activities prior to acetaminophen injection. After acetaminophen challenge, the elevations in plasma alanine aminotransferase activity and histological changes in the liver were ameliorated by EGCG treatment. EGCG reduced acetaminophen-induced apoptosis by lowering the Bax/Bcl2 ratio in the liver. EGCG mildly increased autophagy by increasing the LC3B II/I ratio. Lower hepatic acetaminophen-glutathione and acetaminophen-protein adducts contents were observed after EGCG treatment. EGCG increased glutathione peroxidase and NAD(P)H quinone 1 oxidoreductase activities and reduced organic anion-transporting polypeptides 1a1 expression in the liver after acetaminophen treatment. Our results indicate that EGCG may reduce oxidative stress and lower the metabolism and toxicity of acetaminophen. The reductions in CYP-mediated acetaminophen bioactivation and uptake transporter, as well as enhanced antioxidant enzyme activity, may limit the accumulation of toxic products in the liver and thus lower hepatotoxicity.

Keywords: acetaminophen; apoptosis; autophagy; bioactivation; cytochrome P-450; epigallocatechin-3-gallate; hepatotoxicity.

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Conflict of interest statement

The authors have no conflict of interest to report.

Figures

Figure 1
Figure 1
Effects of EGCG on membrane transporters in the livers of rats. Densitometry quantitation of membrane transporter protein (Mrp2/3 and p-glycoprotein, p-gp) levels from rats fed the EGCG diet for four weeks. Each lane represents the pooled liver membrane protein from five to six individual rats per group. The protein band was quantified by densitometry, and the level of the control was set at 1. EGCG, epigallocatechin-3-gallate. * Significantly different from control group, p < 0.05.
Figure 2
Figure 2
Effects of EGCG supplementation (0.6%) on APAP-induced hepatotoxicity in rats. Histopathological examination of livers was shown in (A) the control group, (B) the APAP group, and (C) the APAP + EGCG group. H&E stain, 400×. Normal architecture of the liver was found in the control group (A). Multifocal necrosis was graded as slight (2) in (B) (APAP group) and minimal (1) in (C) (APAP + EGCG group). Plasma alanine aminotransferase (ALT) activity and hepatic reduced- glutathione (GSH) and GSH peroxidase activity were shown in (D–F), respectively. * Significantly different from control group, p < 0.05. # Significantly different from APAP group, p < 0.05.
Figure 3
Figure 3
Effects of EGCG on APAP-induced apoptosis (Bax/Bcl2) and autophagy (LC3B II/ILC3B I) in the rat liver (A). β-actin served as the loading control. Values are given as the mean ± S.D. (n = 3). Densitometric analysis for Bax/Bcl2 (B) and LC3B II/ILC3B I (C) protein levels is shown. APAP, N-acetyl-p-aminophenol. * Significantly different from control group, p < 0.05. # Significantly different from APAP group, p < 0.05. a Significantly different from APAP group, p < 0.1.
Figure 4
Figure 4
Densitometry quantitation of Mrp2/3, p-gp, and OATP1a1 protein expression from rats fed an EGCG diet for four weeks and then treated with APAP for 12 h. Each lane represents the pooled (n = 5–6) liver membrane protein from an individual rat. The protein band was quantified by densitometry, and the level of the control was set to 1. * Significantly different from control group, p < 0.05. # Significantly different from APAP group, p < 0.05.
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