Oxidative stress mediated idiosyncratic drug toxicity

Area of Science:

• Pharmacology and Toxicology
• Drug Metabolism and Safety Assessment
• Oxidative Stress Mechanisms

Background:

• Drug-induced cytotoxicity is often linked to macromolecular covalent binding or oxidative stress.
• While cytochrome P450 enzymes are key in drug metabolism, peroxidases can also activate xenobiotics, especially in low P450 environments.
• Inflammation significantly enhances oxidative stress through immune cell activation (e.g., Kupffer cells) and reactive oxygen species generation.

Purpose of the Study:

• To develop and validate a novel screening method for new chemical entities (NCEs) to predict oxidative stress and cytotoxicity.
• To investigate the role of inflammation in modulating drug-induced toxicity and prooxidant radical formation.
• To explore the mechanisms by which peroxidases contribute to drug toxicity, particularly in inflammatory conditions.

Main Methods:

• Utilized accelerated molecular cytotoxic mechanism screening (ACMS) techniques with isolated rat hepatocytes.
• Assessed the formation of prooxidant radicals upon drug metabolism and the induction of oxidative stress in intact cells.
• Simulated inflammatory conditions by adding peroxidase/H2O2 to hepatocyte incubates to evaluate drug cytotoxicity and radical formation (glutathione/lipid oxidation).

Main Results:

• The ACMS method demonstrated that cytotoxicity is initiated by macromolecular covalent binding or oxidative stress.
• Peroxidases, particularly in inflamed tissues with activated immune cells, can catalyze xenobiotic oxidation leading to toxicity.
• Inflammation significantly increased the cytotoxicity and prooxidant radical formation of several known hepatotoxic drugs (e.g., troglitazone, diclofenac), while some others (e.g., entacapone) remained non-toxic.

Conclusions:

• A novel screening assay effectively identifies NCEs capable of inducing oxidative stress and cytotoxicity, especially under inflammatory conditions.
• Drug-induced toxicity and carcinogenesis can be mediated by prooxidant free radicals formed via peroxidase activity.
• Sporadic inflammatory episodes during drug therapy may contribute to idiosyncratic hepatotoxicity and recent drug withdrawals from the market.