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Chronic exposure of rodents to perchloroethene (PER) increased the incidence of liver tumors in male mice and resulted in a small but significant increase in the incidence of renal tumors in male rats. The tumorigenicity of PER is mediated by metabolic activation reactions. PER is metabolized by cytochrome P450 and by conjugation with glutathione.(More)
A sensitive and specific liquid chromatography-mass spectrometry (LC-MS) method based on the combination of constant neutral loss scans (CNL) with product ion scans was developed on a linear ion trap. The method is applicable for the detection and identification of analytes with identical chemical substructures (such as conjugates of xenobiotics formed in(More)
Ochratoxin A is a nephrotoxic and tumorigenic mycotoxin which contaminates a variety of food items, resulting in chronic human exposure. Biotransformation reactions have been implicated in the tumorigenicity of ochratoxin A. The biotransformation of ochratoxin A by cytochromes P450 and other mammalian enzymes was investigated to optimize conditions for(More)
Troglitazone, a thiazolidinedione (TZD) type insulin sensitizer for the treatment of diabetes, was withdrawn from the U.S. market after several fatal cases of hepatotoxicity. Although the mechanism(s) of these idiosyncratic adverse reactions are not completely understood, circumstantial evidence suggests at least a partial contribution of reactive(More)
Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests(More)
Hexachlorobutadiene (HCBD) is nephrotoxic in rats causing damage to the proximal tubules. Renal toxicity is presumed to be due to bioactivation by glutathione S-conjugate formation and further processing by the enzymes of the mercapturic acid pathway to reactive intermediates. Recent studies revealed major sex-dependent differences in the pattern of urinary(More)
Isoprostanes are formed after peroxidation of arachidonic acid and are promising biomarkers for reactive oxygen species. A LC-MS/MS based method was developed for the quantitation of two isoprostanes (iPF2alpha-III and 8,12-iso-iPF2alpha-VI) in hepatocytes, tissue and urine samples of rats. A column switching method was used to reduce sample preparation to(More)
In the last decade an important role for the progression of neuronal cell death in Alzheimer's disease (AD) has been ascribed to oxidative stress. trans-4-Hydroxy-2-nonenal, a product of lipid peroxidation, forms conjugates with a variety of nucleophilic groups such as thiols or amino moieties. Here we report for the first time the quantitation of(More)
Computational tools for predicting toxicity have been envisaged for their potential to considerably impact the attrition rate of compounds in drug discovery and development. In silico techniques like knowledge-based expert systems (quantitative) structure activity relationship tools and modeling approaches may therefore help to significantly reduce drug(More)
Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to(More)