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1-Nitropyrene (1-NP) and 1,8-dinitropyrene (1,8-DNP) are diesel exhaust constituents and are classified by the International Agency for Research on Cancer as probable (Group 2A) or possible (Group 2B) human carcinogens. These nitroarenes undergo metabolic activation by nitroreduction to result in the formation of DNA adducts. Human aldo-keto reductases (AKRs) 1C1-1C3 catalyze the nitroreduction of 3-nitrobenzanthrone (3-nitro-7

Often guided by analogy with non phospholipid products from oxidative cleavage of polyunsaturated fatty acids (PUFAs), we previously identified a variety of biologically active oxidatively truncated phospholipids. Previously, 4,5-epoxy-2(E)-decenal (4,5-EDE)1 was found to be produced by oxidative cleavage of 13-(S)-hydroperoxy-9,11-(Z,E)-octadeca-dienoic acid (13-HPODE). 4,5-EDE reacts with deoxy-adenosine (dAdo) and deoxy-guanosine (dGuo) to form mutagenic etheno derivatives. We hypothesized that a functionally similar and potentially mutagenic compound, i.e., 13-oxo-9,10-epoxytridecenoic acid (OETA) would be generated from 9-HPODE through an analogous fragmentation. We expected that an ester of 2-lysophosphatidylcoline (PC), OETA-PC, would be produced by oxidative cleavage of 9-HPODE-PC in biological membranes. An efficient, unambiguous total synthesis of trans-OETA-PC was first executed to provide a standard that could facilitate the identification of this phospholipid epoxyalkenal that was shown to be produced during oxidation of the linoleic acid ester of 2-lysoPC. Finally, trans-OETA-PC was detected in a lipid extract from rat retina. The identity of the naturally occurring oxidatively truncated phospholipid was further confirmed by derivatization with methoxylamine that produced characteristic mono and bis adducts. The average amount of trans-OETA-PC in rat retina, 0.33 pmol, is relatively low, compared to other oxidatively truncated PCs, e.g., the 4-hydroxy-7-oxohept-5-enoic acid PC ester (HOHA-PC, 2.5 pmol) or the 4-keto-7-oxohept-5-enoic acid PC ester (KOHA-PC, 1.7 pmol), derived from the docosahexaenoic acid ester of 2-lysoPC. This, most likely, is because docosahexaenoate PCs are particularly abundant in the retina compared to the linoleate PC ester precursor of OETA-PC. As predicted by analogy with 4,5-EDE, OETA-PC reacts with dAdo and dGuo, as well as with DNA, to form mutagenic etheno-adducts.

Isolevuglandins (isoLGs) are a family of γ-ketoaldehydes, aka isoketals or neuroketals, that are generated by free radical-induced oxidation of polyunsaturated fatty acid-containing lipids. Because of their high reactivity toward e-amino groups of lysyl residues, isoLGs are found as protein adducts in vivo. Plasma levels of isoLG-derived protein modifications are orders of magnitude higher than levels of the corresponding isoprostane. This suggests that while isoprostanes are rapidly cleared from the circulation, isoLG−protein adducts accumulate over the lifetime of the protein, which can be weeks, and this may provide a dosimeter for oxidant stress. We now confirm the postulated formation of the first D series isoLG, iso[7]LGD2, by free radical-induced oxidation of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine in vitro. We also show that iso[7]LGD2−protein adduct levels in blood are the highest known for an isoLG-derived epitope. They average 30-fold higher than isoLGE2−protein and 3-fold higher ...

Oxidized (ox) phospholipids are receiving growing recognition as important messengers in oxidative stress signaling pathways and as endogenous electrophilic toxins that interfere with protein function through covalent modifications. Phosphatidylcholine lipids predominate in low-density lipoproteins (LDL). Our previous studies of oxLDL identified a family of biologically active oxidatively truncated phosphatidylcholines that are also present in atherosclerotic plaques. In contrast, phosphatidylethanolamine (PE) lipids are extraordinarily abundant in retina. Because photoreceptors contain the most highly unsaturated fatty acids found in vertebrate tissues, these membranes are expected to be especially susceptible to oxidative damage. Here, we report that oxidatively truncated ethanolamine phospholipids (oxPEs) are present in retina. As expected, the most abundant oxPEs, succinyl (2.2 +/- 0.8 pmol/retina) and omega-oxobutyryl (1.5 +/- 1.0 pmol/retina) esters of 2-lysophosphatidylethanolamine, are derived from the docosahexaenoyl ester, the most abundant polyunsaturated PE in retina. However, a large amount of the omega-oxononanoyl ester (1.3 +/- 0.6 pmol/retina), derived from linoleyl-PE, is also present even though linoleate is an order of magnitude less abundant than docosahexenoate in retina. There is a notable trend for the presence in retina of greater amounts, relative to the levels of their precursors, of longer chain homologous aldehydes and alkanedioate monoesters. We considered the possibility that this trend results from differences in the proclivities of various polyunsaturated fatty acyl (PUFA)-PEs to generate these homologous products. Therefore, we examined oxidative cleavage of various PUFA-PEs in small unilamellar vesicles. Alkanedioate monoesters are the major stable end products. Particularly notable is the fact that omega-oxononanoyl-PE levels either do not decline or decline less than those of the analogous aldehydes omega-oxobutyryl-PE or omega-oxovaleryl-PE during autoxidation for 33 h. The resistance of omega-oxononanoyl-PE, as compared with omega-oxobutyryl-PE and omega-oxovaleryl-PE, to further oxidation may contribute to the greater amount of this oxPE relative to its precursor, linoleyl-PE, in retina.