Oxidative Stress Mediated Idiosyncratic Drug Toxicity

Abstract

The following describes a novel screening method for "new chemical entities" (NCEs), suitable for ADMET studies, that measures ability to form prooxidant radicals on metabolism and their ability to induce oxidative stress in intact cells. The accelerated molecular cytotoxic mechanism screening (ACMS) techniques used with isolated rat hepatocytes showed that cytotoxicity is usually initiated as a result of macromolecular covalent binding or macromolecular oxidative stress. While P450 is likely responsible for drug metabolic activation in the liver, intestine, lung, and in other nonhepatic tissues, where P450 levels are low, peroxidases including prostaglandin synthetase peroxidase can catalyze xenobiotic one-electron oxidation to form prooxidant free radicals that may cause toxicity or carcinogenesis. Inflammation markedly activates H2O2, generating NADPH oxidase and peroxidase of certain immune cells when they infiltrate tissues including the liver. Myeloperoxidase and NADPH oxidase in the Kupffer cells (resident macrophages of the liver) also become activated during inflammation. The addition of noncytotoxic concentrations of peroxidase/H2O2 to the hepatocyte incubate markedly increased drug cytotoxicity and prooxidant radical formation as shown by glutathione or lipid oxidation. Many drugs that have hepato- or gastrointestinal (GI) toxicity problems or were withdrawn from the market for safety problems, e.g., troglitazone, tolcapone, mefenamic acid, diclofenac, and phenylbutazone, were markedly more toxic and prooxidant in this inflammation model system, whereas other drugs, e.g., entacapone, were not toxic in this inflammation model. Some of the idiosyncratic hepatotoxicity responsible for recent drug withdrawals may therefore result from commonplace sporadic inflammatory episodes during drug therapy.

Development of a Convenient In Vivo Hepatotoxin Assay Using a Transgenic Zebrafish Line with Liver-Specific DsRed Expression

“…Isoniazid is known to cause oxidative stress and apoptosis in the liver [16], [17]. Phenylbutazone is a poisonous toxin as well as a hepatotoxin with severe oxidative stress in the liver [18]. Indeed we observed dosage-dependent decreases of both red fluorescence intensity in the liver and the size of the liver by treatment with the four established hepatotoxins.…”

Protective Effects of N-acetylcysteine and a Prostaglandin E1 Analog, Alprostadil, Against Hepatic Ischemia: Reperfusion Injury in Rats

“…Recent evidence indicates that reactive oxygen metabolites play a fundamental role in the hepatotoxicity due to various xenobiotics and medications. [343536] Lipid peroxidation is known to play an essential role in damaging the cell membrane through reactive oxygen radicals. I/R injury has been shown to increase MDA levels, which is an important index of lipid peroxidation.…”

Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients

“…In contrast, previously reported promoter SNP rs17883901 and 5’UTR GAG trinucleotide polymorphisms [33-35] did not show significant associations. Although reactive metabolites and oxidative stress were proposed to be involved in the pathogenesis of idiosyncratic drug reactions [4,5,36], this is the first study implicating a gene involved in antioxidant defense, affecting risk of idiosyncratic drug-induced cutaneous reactions.…”