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    • The oxidation of lipids proteins nucleic acids

    2018-11-12

    The oxidation of lipids, proteins, nucleic acids and carbohydrates generate a variety of damaging breakdown products which thus can lead to the onset of many degenerative diseases [11–15,62,63,69]. Lipid peroxidation of cell structures containing lipids can lead to the generation of different toxic products, including alcohols, ketones, alkanes, aldehydes and ethers which have the potential to contribute to cell damage, necrosis or apoptosis [26,63,70–72]. For proteins thiolgroups of cysteine residues are the most sensitive targets of ES. Redox-dependent modifications of intra- and intermolecular disulfide bonds can lead to structural/functional changes and protein aggregation [12,24,62,73–76]. Altogether these ROS-induced damages may cause malfunctioning enzymes, transporters, signal transducers or structural proteins. Nucleic acids are delicate targets of ES leading to mutations. Damage of nucleic acids by ES may result in single and double strand breaks, DNA–DNA, DNA–protein, DNA–lipid adducts or numerous sitagliptin phosphate modifications such as 8-hydroxy-deoxyguaonosine, 5-hydroxylmethyluracil, 8-hydroxydeoxyadenine and thyminglycol [12,19,24,77–80]. Mitochondrial DNA (mtDNA) is particularly susceptible to oxidative damage because of the absence of associated histones, an incomplete mitochondrial DNA repair system and the generation of free radicals through electron leakage from the respiratory chain [78–80]. Interestingly, carbohydrate oxidation may also be involved in DNA damage, as oxidation and fragmentation of deoxyribose fragments produced from DNA by free-radical attack are believed to play a major role in mutations by blocking the action of DNA polymerase and DNA ligase [19,27,58,81].
    Several in vitro biochemical assessment systems are focused either on the measurements of primary or secondary products derived from oxidized lipids, proteins, nucleic acids and carbohydrates or the integrity or activity of a variety of key biomolecules which play major roles in cell integrity, metabolism, signaling pathways, gene expression and translation [3,11–15,62,63]. Testing whether a chemical can modulate the activity of particular enzyme or binding affinities to a particular receptor or other biomolecule is the most direct way to gain mechanistic insights into action at the molecular level. There are different biochemical in vitro assays which analyze the integrity or mutation of DNA and RNA, membrane lipids, as well as the binding and activity of various receptors, enzymes involved in signaling transduction, drug or neurotransmitter metabolism and many others [3–6,24,25,27–29]. The risk assessment of genotoxicity by DNA-reactive toxicants in food is of particular interest by virtue of the close correlation with carcinogenesis [24,82,83]. To measure the potential for genotoxic activity of food compounds which might lead to mutations traditionally the Ames bacterial reverse mutation test is used [84]. The Ames test is based on the growth of several histidine dependent Salmonella strains carrying different mutations in various genes of the histidine operon [6,27,85]. Other methods measuring genotoxic potential in cell-based systems are discussed below. A variety of enzyme and receptor-binding assays have been developed to examine specific mechanisms of action at the molecular level of different receptors (e.g. ion channels, G-protein coupled receptors, tyrosine kinases, nuclear receptors), signaling transduction enzymes (kinases, proteases, phosphatases, phosphodiesterases), and enzymes metabolizing drugs (e.g. cytochrome P450 monooxygenases) or neurotransmitters (e.g. acetylcholinesterase). As in vitro prescreening tools the human ether-a-go-go-related gene (hERG) potassium ion channel [86–88] or acetylcholinesterase activity assay [89,90] are routinely used for a global assessment of cardiotoxicity or neurotoxicity, respectively. Other assays monitor the potential effects of toxicants which interfere with anti-inflammatory drugs. These may utilize a high-throughput screening for microsomal prostaglandin E synthase activity [91].