Troglitazone Hepatotoxicity: Are We Getting Closer to Understanding Idiosyncratic Liver Injury?

Idiosyncratic hepatotoxicity is a rare and unpredictable event of liver injury affecting generally less than 1 in 10,000 patients treated with certain drugs. However, it is a serious clinical problem as it accounts for 10% of all drug-induced liver failure cases (Kaplowitz, 2005). Since idiosyncratic drug reactions are not detected in preclinical testing and in most cases not even during clinical trials, the problem surfaces generally after the drug is approved and hundreds of thousands of patients are being treated. Idiosyncratic hepatotoxicities are currently the main cause for Food and Drug Administration-mandated warnings, restrictions of use or even withdrawals of drugs from the market (Kaplowitz, 2005). As such, this is a considerable problem for the pharmaceutical industry and for regulatory agencies worldwide. One of the recent examples of drugs causing idiosyncratic hepatotoxicity and liver failure was the antidiabetic drug Rezulin (troglitazone). Troglitazone, a peroxisome proliferator–activated receptor gamma agonist, which enhances insulin sensitivity, was approved for the treatment of type 2 diabetes in 1997. Troglitazone was an effective antidiabetic drug with a fundamentally new mechanism of action. However, within a year after its widespread use, individual cases of liver injury and failure were reported (Watkins, 2005). The mounting evidence for the idiosyncratic hepatotoxicity of troglitazone in the following years and the development of rosiglitazone and pioglitazone, drugs with a similar mechanism of action but presumably without the liver liabilities, led to the withdrawal of troglitazone from the market in the year 2000. Since then, a considerable effort has been made to elucidate the mechanism of troglitazone-induced hepatotoxicity. A number of hypotheses were brought forward to explain troglitazone-induced cell injury including the formation and accumulation of toxic metabolites, mitochondrial dysfunction and oxidant stress, inhibition of the bile salt transporter and bile acid toxicity, and the induction of apoptosis (Choijker, 2005). However, virtually all the studies were performed with cultured cell lines using concentrations of troglitazone 1–2 orders of magnitude above pharmacological levels. Thus, these in vitro studies could not provide a relevant mechanistic explanation for troglitazone hepatotoxicity in patients (Choijker, 2005). Nevertheless, some of these experiments demonstrated that high concentrations of troglitazone can induce mitochondrial dysfunction in these cell lines (Haskins et al., 2001; Tirmenstein et al., 2002). Furthermore, troglitazone, but not rosiglitazone or pioglitazone, was able to induce the mitochondrial membrane permeability transition pore opening in isolated rat liver mitochondria (Masubuchi et al., 2006). Although these mechanisms appear not to be relevant for damage in normal hepatocytes in vivo, it raises the possibility that under certain conditions troglitazone has the potential to cause a mitochondrial stress. The currently favored concept of idiosyncratic hepatotoxicity assumes that the injury is caused by a combination of certain genetic and environmental factors, which sufficiently enhance an individual’s susceptibility to otherwise clinically silent adverse effects of a drug (Watkins, 2005). This may more likely develop into a problem when the cellular stress caused by the drug superimposes with the stress of the disease to be treated (Boelsterli, 2003). For example, obesity, diabetes, and steatosis result in a chronic oxidant stress and mitochondrial dysfunction (Pessayre et al., 2001), which may enhance the toxicity of drugs that target mitochondria, e.g., acetaminophen (Jaeschke and Bajt, 2006). In fact, acetaminophen hepatotoxicity is significantly aggravated in obese and diabetic mice (Kon et al., 2005). Mitochondrial dysfunction is generally accompanied by enhanced reactive oxygen formation. A critical defense against mitochondrial oxidant stress is the mitochondrial enzyme manganese superoxide dismutase (MnSOD, SOD2). SOD2-deficient mice (SOD2 / ) die within a few days after birth underscoring the critical 1 For correspondence via e-mail: hjaeschke@kumc.edu.