Lipid hydroperoxides are formed in vivo through free radical pathways from the action of reactive oxygen species on polyunsaturated fatty acids. They are also formed as specific products of lipoxygenases and cyclooxygenases. Homolytic decomposition of lipid hydroperoxides to the alpha,beta-unsaturated aldehyde genotoxins, 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal occurs through two quite distinct pathways. One pathway involves a complex rearrangement of the alkoxy radical derived from the lipid hydroperoxide and the other pathway involves the intermediate formation of another potential genotoxin, 4-hydroperoxy-2-nonenal. 4,5-Epoxy-2(E)-decenal forms the unsubstituted etheno-2-deoxyadenosine adduct with DNA, a mutagenic lesion which has been observed in human tissue DNA samples. Several new ethano- and etheno-DNA-adducts have been identified from the reaction of 4-oxo-2-nonenal with DNA. 4-Hydroxy-2-nonenal forms propano adducts with 2'-deoxyguanosine. It can also up-regulate cyclooxygenase-2 expression. As cyclooxygenase-2 converts linoleic acid into lipid hydroperoxides, this provides a potential mechanism for increased production of genotoxic bifunctional electrophiles. Malondialdehyde (beta-hydroxy-acrolein), another genotoxic bifunctional electrophile, is formed during homolytic decomposition of lipid hydroperoxides that contain more than two double bonds. Other sources of malondialdehyde include, hydroxyl radical-mediated decomposition of the 2'-deoxyribose DNA backbone and formation as a side-product during the biosynthesis of thromboxane A(2). Malondialdehyde reacts with DNA to form primarily a propano adduct with 2'-deoxyguanosine (M(1)G-dR). Significant advances in the characterization and analysis of lipid hydroperoxide-derived endogenous DNA-adducts have been made over the last decade so that dosimetry studies of human populations are now possible. Such studies will help elucidate the role of lipid hydroperoxide-derived endogenous DNA as mediators of cancer,
"This then potentially implicates etheno or indeed other MPG substrates  as lesions that may be recognised by, the MutS homolog, MSH2 as MutS from Escherichia coli recognises exocyclic adducts arising from exposure to malondialdehyde . Both t-BOOH  and KBrO3  treatments can increase lipid peroxidation and potentially increase etheno DNA adducts, so that there does not seem to be a simple correlation between the persistence or absence of etheno DNA adducts and cellular response following Msh2 knockdown. However, this does not rule out the possibility that the different treatments used result in differing levels of etheno adducts and/or that KBrO3 results in a lesion whose persistence is directly cytotoxic irrespective of MSH2 function, whereas t-BOOH forms predominantly lesions whose toxicity is MSH2 dependent. "
[Show abstract][Hide abstract] ABSTRACT: The DNA mismatch repair (MMR) and base excision repair (BER) systems are important determinants of cellular toxicity following exposure to agents that cause oxidative DNA damage. To examine the interactions between these different repair systems, we examined whether toxicity, induced by t-BOOH and KBrO3, differs in BER proficient (Mpg (+/+), Nth1 (+/+)) and deficient (Mpg (-/-), Nth1 (-/-)) mouse embryonic fibroblasts (MEFs) following Msh2 knockdown of between 79 and 88% using an shRNA expression vector. Msh2 knockdown in Nth1 (+/+) cells had no effect on t-BOOH and KBrO3 induced toxicity as assessed by an MTT assay; knockdown in Nth1 (-/-) cells resulted in increased resistance to t-BOOH and KBrO3, a result consistent with Nth1 removing oxidised pyrimidines. Msh2 knockdown in Mpg (+/+) cells had no effect on t-BOOH toxicity but increased resistance to KBrO3; in Mpg (-/-) cells, Msh2 knockdown increased cellular sensitivity to KBrO3 but increased resistance to t-BOOH, suggesting a role for Mpg in removing DNA damage induced by these agents. MSH2 dependent and independent pathways then determine cellular toxicity induced by oxidising agents. A complex interaction between MMR and BER repair systems, that is, exposure dependent, also exists to determine cellular toxicity.
"LOOHs decompose to malondialdehyde (MDA). LOOHs, such as 4,5-epoxy-2(E)-decenal and 4-hydroxy- 2-nonenal, as well as MDA, are genotoxic via oxidative reactions and lead to the formation of DNA adducts that are involved in the pathogenesis of tobacco smoke–related cancers and cardiovascular disease (Blair 2001; Nair et al. 2007a; Yanbaeva et al. 2007). Oxidative stress and the consequent lipid peroxidation also have potential roles in the pathogenesis of more than 30 other smoking-related diseases, including cerebrovascular disorders, chronic obstructive pulmonary diseases, and diabetes (Banerjee et al. 1998; Fahn et al. 1998; Altuntas et al. 2002). "
[Show abstract][Hide abstract] ABSTRACT: Food plants provide important phytochemicals which help improve or maintain health through various biological activities, including antioxidant effects. Cigarette smoke-induced oxidative stress leads to the formation of lipid hydroperoxides (LOOHs) and their decomposition product malondialdehyde (MDA), both of which cause oxidative damage to DNA. Two hundred forty-five heavy cigarette smokers completed a randomized, double-blind, placebo-controlled clinical trial designed to investigate the effect of noni juice on LOOH- and MDA-DNA adducts in peripheral blood lymphocytes (PBLs). Volunteers drank noni juice or a fruit juice placebo every day for 1 month. DNA adducts were measured by (32)P postlabeling analysis. Drinking 29.5-118 mL of noni juice significantly reduced adducts by 44.6-57.4%. The placebo, which was devoid of iridoid glycosides, did not significantly influence LOOH- and MDA-DNA adduct levels in current smokers. Noni juice was able to mitigate oxidative damage of DNA in current heavy smokers, an activity associated with the presence of iridoids.
"considerably more reactive than aldehydes with proteins and have shown cytotoxicity (Vock et al., 1999) as well as carcinogenicity (Van Duuren, 1966; Chung et al., 1993; Blair, 2001; Lee et al., 2001), genotoxicity (Ehrenberg & Hussain, 1981; von der Hude et al., 1992; Hemminki et al., 1994), and mutagenicity (Lee et al., 2002). Epoxides have been identified as dominant or sole products in neat oils or aprotic solvents (Gardner et al., 1974, 1978, 1985; Gardner, 1989; Haynes & Vonwiller , 1990), and we have observed the same in methyl linoleate model systems (Xie & Schaich, 2012). "
Lipid Oxidation: Challenges in Food Systems, Edited by U. Nienaber, A. Logan, X. Pan, 01/2013: chapter Challenges in analyzing lipid oxidation: Are one product and one sample concentration enough?: pages 53-128; AOCS Press.
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