## 3 Lipid Peroxidation
\(\alpha\),\(\beta\)-Unsaturated aldehydes, such as 2-ocreal, 2-nonenal, and 4-HNE (aldehydes formed in Figures 2 and 3), are also more reactive than saturated counterparts, as they are electrophilic at both the carbonyl carbon and the \(\beta\)-carbon and able to undergo both 1,2- and 1,4-addition reactions [47]. Unsaturated aldehydes react with nucleophilic moieties of proteins and nucleic acids, modifying those molecules and effecting their function [36]. Substitution at the \(\gamma\)-carbon (4-position), as in 4-HNE and 4-hydroxy-2-hexenal (4-HHE), somewhat diminishes 1,4-addition reactivity due to steric and electronic considerations and thus confers a longer lifetime [48]. Indeed, 4-HNE is among the most detected and studied LPO products [49; 50]. Figure 2: Polyunsaturated fatty acyl sidechain oxidation via free radical-mediated hydro-peroxide formation and decomposition leads to mixtures of saturated and unsaturated aldehydes (ROS = reactive oxygen species; LH = neighboring lipid). Atoms in red give rise to the aldehydes generated on hemiacetal equilibrium. Figures 2 and 3 illustrate the mixture of aldehydes and aldehyde types that can be formed under LPO conditions. The application of this process to a wider, representative selection of \(\omega\)-3, -6, -7, and -9 unsaturated FAs taken from Table 1 creates a diverse panel of aldehydes, listed in Table 2, a result of the random nature of LPO. Efforts that have experimentally mimicked LPO conditions in vitro on MUFAs and PUFAs report many of these aldehydes. [PERSON] et al. carried out oxidations of mono- and polyunsaturated fatty acids with Fe(II) and hydrogen peroxide at 37 \({}^{\circ}\)C and found all but two of the \(\alpha\),\(\beta\)-unsaturated aldehydes listed in Table 2 [51]. In 2007, [PERSON] et al. reported 33 aldehyde products from in vitro lipid peroxid oxidations at pH 7.4 and 37 \({}^{\circ}\)C matching four of the seven \(\alpha\),\(\beta\)-unsaturated aldehydes and four of the five hydroxylalehydes listed in Table 2 [52]. \begin{table}
\begin{tabular}{c c c c} \hline \hline \multirow{2}{*}{**Fatty Acid Sidechain**} & \multicolumn{3}{c}{**Aldehydes Predicted as LPO Products**} \\ \cline{2-4}  & **Saturated** & **Unsaturated** & **Hydroxy** \\ \hline \multirow{4}{*}{\(\omega\)-3} & \multirow{4}{*}{\(\alpha\)-1 inolic acid (\(\Delta^{9,12,15}\))} & 2-pental & \multirow{2}{*}{2-hydroxybutanal} \\  & & & \\ \cline{1-1} \cline{5-5}  & & & 4-hydroxyhexneal (4-HHE) \\ \cline{1-1} \cline{5-5}  & & & 2-octan \\ \cline{1-1} \  
Not shown in Table 2 are several low-molecular weight (C1-C3) aldehydes arising from lipid over-oxidation, secondary aldehyde oxidations, or amino acid metabolism; these include formaldehyde, acetaldehyde, hydroxyacetaldehyde, propenal (acrolein), and malondialdehydedehyde (MDA). With the exception of MDA, these aldehydes are common in breath, often as a result of alcohol and tobacco use [53; 54], and as such are not reliable as biomarkers of lung cancer. MDA, however, is a product of LPO and a well-established [55] marker of OS and will be discussed in a later section. Hydroxyacetaldehyde, a reported marker of lung cancer [56], is more closely linked to serine metabolism than lipid peroxidation [57; 58].