Animal models of drug-induced liver injury

Abstract

Drug-induced liver injury (DILI) presents unique challenges for consumers, clinicians, and regulators. It is the most common cause of acute liver failure in the US. It is also one of the most common reasons for termination of new drugs during pre-clinical testing and withdrawal of new drugs post-marketing. DILI is generally divided into two forms: intrinsic and idiosyncratic. Many of the challenges with DILI are due in large part to poor understanding of the mechanisms of toxicity. Although useful models of intrinsic DILI are available, they are frequently misused. Modeling idiosyncratic DILI presents greater challenges, but promising new models have recently been developed. The purpose of this manuscript is to provide a critical review of the most popular animal models of DILI, and to discuss the future of DILI research.

Keywords: Acetaminophen; Carbon tetrachloride; Idiosyncratic hepatotoxicity; Immune tolerance; Intrinsic hepatotoxicity.

Figure 1.. Mechanisms of Acetaminophen Hepatotoxicity.

Acetaminophen (APAP) hepatotoxicity begins with formation of a reactive metabolite (NAPQI) that binds to proteins. Binding to mitochondrial proteins causes mitochondrial dysfunction and oxidative stress. The initial reactive oxygen species (ROS) activate kinases like the c-Jun N-terminal kinases 1/2 (Jnk), which then exacerbates the mitochondrial oxidative stress. Eventually, the mitochondrial permeability transition (MPT) occurs and mitochondrial polarization and ATP production are lost. The mitochondrial matrix swell and the outer membranes rupture releasing endonucleases (EndoG and AIF) that translocate to the nucleus and fragment nuclear DNA.

Figure 2.. Mechanisms of Carbon Tetrachloride Hepatotoxicity.

Carbon tetrachloride (CCl₄) is converted to a radical (CCl₃·) that binds to proteins, DNA and lipids. This causes mitochondrial damage and oxidative stress. CCl₃· can also react with O₂ to form CCl₃OO·, which initiates the lipid peroxidation (LPO) chain reaction that damages cell membranes.

Figure 3.. Importance of Immune Tolerance in Idiosyncratic DILI.

In WT C57Bl/6 mice, daily treatment with idiosyncratic hepatotoxicants causes delayed-onset transient liver injury. In the Uetrecht-Pohl model, various strategies are used to reduce regulation of the adaptive immune system and therefore prevent development of immune tolerance, and those mice experience ongoing liver injury. Results from that model have demonstrated that immune tolerance is a likely explanation for the transient nature of most IDILI in humans; loss of tolerance may explain why only some cases of IDILI are severe.