Isoniazid-induced liver injury and immune response in mice

Abstract

Isoniazid (INH) is associated with one of the highest incidences of idiosyncratic drug-induced liver failure of any commonly prescribed drug. The mechanism of this liver injury remains uncertain, and a valid animal model would greatly facilitate mechanistic studies. Most studies of INH-induced liver toxicity have been acute studies performed in rats with high doses of the drug, and this is very different from the idiosyncratic liver injury that occurs in humans. It has previously been demonstrated that covalent binding of INH in the liver of mice is greater than in rats and more like that in humans. Therefore, mice should be a better species in which to develop an animal model of INH-induced liver injury. Treatment of Cbl-b À/À and PD1 À/À mice, which have impaired immune tolerance, resulted in greater injury than their C57BL/6 background, but not liver failure. This suggested that the injury was mediated by the adaptive immune system; however, Rag À/À mice, which do not have competent T-and B-cells, sustained more liver injury than C57BL/6 wild-type mice. This suggested that the adaptive immune system also played a protective role. INH treatment also led to a decrease in the inflammatory cytokines IL-1a and IL-12, which suggests that the drug may have immunosuppressive properties. In short, a mouse model was developed of INH-induced liver injury in which the immune system appears to play a both protective and pathogenic role, but this study was unable to develop a model of INH-induced liver failure.

Mechanisms of isoniazid‐induced idiosyncratic liver injury: Emerging role of mitochondrial stress

“…Only an animal model with a specific underlying predisposing condition (genetic, acquired) can likely mimic the situation of patients carrying these susceptibility factors (see below). However, even in mice strains with genetically impaired immune tolerance (Cbl‐b −/− and PD1 −/− mice), the clinical pattern of liver failure could not be recapitulated …”

Mechanistic biomarkers in acetaminophen-induced hepatotoxicity and acute liver failure: from preclinical models to patients

“…Idiosyncratic hepatotoxicity is especially difficult to study due to its rarity. Considerable effort has been made to predict and model drug-induced liver injury in humans using laboratory animals [105,106,107,108] with only little success and even with some controversy [109]. APAP hepatotoxicity in rodents is increasingly popular as an experimental model of drug-induced liver injury because it is relatively well-characterized, clinically relevant, and convenient.…”

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

“…Studies of the hepatotoxic mechanisms of INH were previously conducted using different animal models; however, results were accompanied by the absence of certain features of INH toxicity, i.e., delayed onset or inconsistency in severity compared to that in hu-mans (3). Despite the lack of success in reproducing the same clinical features of INH hepatotoxicity, our group in a previous study successfully established an animal model that could fill the gap associated with understanding the whole picture.…”

“…Despite the fact that INH has been widely used as a first-line antitubercular agent (2,3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4,5). Although the pathophysiology of INH-induced liver injury might vary, the toxicity features of the drug, including hepatocellular steatosis, necrosis, and inflammatory infiltration, are nearly consistent (6,7).…”