Weaning Mice and Adult Mice Exhibit Differential Carbon Tetrachloride-Induced Acute Hepatotoxicity.

Tae Bin Jeong,Yun-Hee Lee,Doyoung Kwon,Seung Won Son,Sou Hyun Kim,Min-Soo Seo,Young-Suk Jung,Kil Soo Kim

doi:10.3390/antiox9030201

Abstract

Age is a risk factor for drug-induced liver injury (DILI). However, there is a limited understanding of pediatric DILI. Here, 2-week-old weaning and 8-week-old adult male ICR mice were intraperitoneally injected with CCl4 (0.1 mmol/kg equal to 15.4 mg/kg) to comparatively evaluate the time-dependent liver damage and cellular events. CCl4 significantly enhanced the serum alanine aminotransferase/aspartate aminotransferase levels and hepatic centrilobular necrosis in the weaning mice, whereas it induced mild liver injury in the adult mice. CCl4-treated weaning mice exhibited higher hepatic levels of pro-apoptotic proteins (Bax, cleaved caspase-3, -7, and -9), activated MAPKs (p-JNK and p-Erk), and endoplasmic reticulum stress indicators (ATF6 and CHOP) and lower hepatic anti-apoptotic Bcl-2 levels than the adult mice. The weaning mice exhibited enhanced basal hepatic glutathione (GSH) levels due to high glutamate cysteine ligase (GCL) and low anti-cysteine dioxygenase (CDO) enzyme levels. However, CCl4 markedly reduced the hepatic GSH levels only in the weaning mice. Furthermore, higher hepatic levels of oxidative stress-induced malondialdehyde, 4-hydroxynonenal, nitrotyrosine-protein adducts, and oxidized proteins were observed in CCl4-treated weaning mice than in CCl4-treated adult mice. The enhanced levels of hepatic cytochrome P450 (CYP) 2E1 and CYP3A, and decreased hepatic GSH S-transferase (GST)-π and GSH reductase (GR) levels in the weaning mice may contribute to their enhanced susceptibility to liver damage.

Highlights

The liver is the primary organ for metabolism of xenobiotics, including toxins, environmental pollutants, chemicals, and drugs [1,2]
The analysis of hematoxylin and eosin (H&E)-stained liver tissues indicated that the weaning mouse liver exhibited severe centrilobular necrosis at 24 h post-CCl4 injection, whereas the adult mouse liver exhibited mild liver injury (Figure 2E)
The results indicated that the differential hepatic levels of cytochrome P450 (CYP), GSH S-transferase (GST)-π, and GSH reductase (GR) proteins mice, that represents infant age before weaning, and 8-week-old mice that represents adulthood

Summary

Introduction

The liver is the primary organ for metabolism of xenobiotics, including toxins, environmental pollutants, chemicals, and drugs [1,2]. Xenobiotics can be detoxified and converted to hydrophilic forms for excretion by phase I and phase II drug-metabolizing enzymes in the liver. Metabolic reactions can generate reactive products to cause liver damage [2]. Drug-induced liver injury (DILI) is the leading cause of acute liver failure and drug withdrawal from the market [3,4]. The risk factors for DILI are age, sex, and genetic polymorphisms [5].

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Discussion

Conclusion