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The order of antioxidant effectiveness of low concentrations of vitamin E analogues, in preventing cumene hydroperoxide-induced hepatocyte lipid peroxidation and cytotoxicity, was 2,2,5,7,8-pentamethyl-6-hydroxychromane (PMC) > troglitazone > Trolox C > alpha-tocopherol > gamma-tocopherol > delta-tocopherol. However, vitamin E analogues, including troglitazone at higher concentrations, induced microsomal lipid peroxidation when oxidized to phenoxyl radicals by peroxidase/H2O2. Ascorbate or GSH was also cooxidized, and GSH cooxidation by vitamin E analogue phenoxyl radicals was also accompanied by extensive oxygen uptake and oxygen activation. When oxidized by nontoxic concentrations of peroxidase/H2O2, vitamin E analogues except PMC also caused hepatocyte cytotoxicity, lipid peroxidation, and GSH oxidation. The prooxidant order of vitamin E analogues in catalyzing hepatocyte cytotoxicity, lipid peroxidation, and GSH oxidation was troglitazone > Trolox C > delta-tocopherol > gamma-tocopherol > alpha-tocopherol > PMC. A similar order of effectiveness was found for GSH cooxidation or microsomal lipid peroxidation but not for ascorbate cooxidation. Except for troglitazone, the toxic prooxidant activity of vitamin E analogues was therefore inversely proportional to their antioxidant activity. The high troglitazone prooxidant activity could be a contributing factor to its hepatotoxicity. We have also derived equations for three-parameter quantitative structure-activity relationships (QSARs), which described the correlation between antioxidant and prooxidant activity of vitamin E ananlogues and their lipophilicity (log P), ionization potential (E(HOMO)), and dipole moment.

Nanotechnology is poised to impact the food and food-related industries through improvements in areas as diverse as production, packaging, shelf life, and bioavailability of food and beverage components. An evaluation was undertaken to characterize the published literature pertaining to the safety of oral exposure to food-related nanomaterials and to identify research needs in this area. Thirty publications were identified in which a toxicological endpoint was assessed following in vivo (oral) or in vitro exposure to food-related nanomaterials. These publications were evaluated for overall quality using a two-step method that determined the reliability of the study design and the extent of nanomaterial characterization within each study. Of the 21 in vivo studies evaluated, 20 used mice or rats, 15 were lacking in some critical component of study design (e.g., oral gavage dose volume was not reported), none was longer than 90 days in duration, and only seven reported more than five physicochemical parameters for the nanomaterial(s) being evaluated. Of the nine in vitro studies evaluated, seven focused on cytotoxicity, two evaluated genotoxicity, only five reported more than five physicochemical parameters for the nanomaterial(s) being evaluated, and none discussed the potential interference by the nanomaterial(s) of the experimental assays that were employed. The results of this evaluation indicate that there is currently insufficient reliable data to allow clear assessment of the safety of oral exposure to food-related nanomaterials. Significant investment must be made to generate studies of sufficient quality and duration and that report comprehensive nanomaterial characterization such that results can be judged reliable and interpretable. Failure to do so will result in the perpetuation of the publication of studies that are inadequate for use in risk characterization.

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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.

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