Routes to 4-hydroxynonenal: fundamental issues in the mechanisms of lipid peroxidation

Abstract

Although investigation of the toxicological and physiological actions of alpha/beta-unsaturated 4-hydroxyalkenals has made great progress over the last 2 decades, understanding of the chemical mechanism of formation of 4-hydroxynonenal and related aldehydes has advanced much less. The aim of this review is to discuss mechanistic evidence for these non-enzymatic routes, especially of the underappreciated intermolecular pathways that involve dimerized and oligomerized fatty acid derivatives as key intermediates. These cross-molecular reactions of fatty acid peroxyls have also important implications for understanding of the basic initiation and propagation steps during lipid peroxidation and the nature of the products that arise.

FIGURE 1.

Comparison of classical and alternative paradigms for the initiation and propagation of lipid peroxidation. In the classical paradigm (upper), the most significant reactions involve single fatty acid molecules, until the final stages. In the alternative paradigm (lower), cross-chain peroxyl radical reactions play an important role during initiation and propagation. It is proposed that subsequent breakdown of these dimers and oligomers expands the pool of radicals that drive the autoxidation reaction and also yields aldehydic carbon chain cleavage products, e.g. HNE.

FIGURE 2.

Enzymatic and non-enzymatic routes to 4-H(P)NE. Left, in the plant lipoxygenase (LOX)-hydroperoxide lyase (HPL) pathway, the 9-hydroperoxide of linoleic acid is cleaved to 3Z-nonenal via rearrangement into an unstable hemiacetal by CYP74C (47). Facile non-enzymatic oxygenation of 3Z-nonenal gives 4-HPNE. Right, autoxidation studies indicate that both the 9- and 13-hydroperoxides of linoleic acid are precursors of 4-HPNE, although the mechanisms remain controversial (12).

FIGURE 3.

Epoxidation of 15S-HETE or 15S-HPETE during thin film autoxidation. The starting hydro(pero)xy group at the ω6 carbon (red ovals) is unchanged in the products. Conversion of 15S-H(P)ETE to 4S-H(P)NE similarly involves retention of the originalω6 hydro(pero)xy group (19). These observations suggested a potential mechanistic connection between formation of the epoxides and carbon chain cleavage; cross-molecular peroxyl radical reactions are implicated (27).

FIGURE 4.

Styrene-oxygen copolymerization and depolymerization. A, the polymerization reaction; B, the depolymerization (unzipping) forms epoxide, benzaldehyde, and formaldehyde.

FIGURE 5.

Illustrative pathways to H(P)NE and other products via dimerization. Step I involves addition of a peroxyl radical to the 11,12-cis-double bond of 15-HPETE, yielding a carbon-centered allyl radical. If the cross-molecular peroxide bond is split at this stage (the side reaction at step II), the products are the 11,12-epoxy-15-hydroperoxide (Ep-OOH) and an alkoxyl radical. This epoxyhydroperoxide represents the type we have isolated and characterized (27). It is also equivalent to the reaction that leads a G526S mutant of COX-2 to arrest prostaglandin synthesis and instead form diepoxyalcohol products (48). Alternatively, proceeding from step II to step III, the allyl radical is oxygenated to a peroxyl, e.g. at C-12 as shown. This peroxyl can be reduced to a hydroperoxide by picking up a hydrogen, giving the dimer (step IV), or it can attack a third molecule of 15-HPETE at the 11,12-double bond (the side reaction at step III). The dimer formed by hydrogen abstraction is prone to breakage of one of the peroxide bonds, particularly the cross-molecular peroxide. This leads in turn to carbon chain cleavage and production of two aldehydes, 11-oxoundeca-5,8-dienoic acid and 4-HPNE. The C-11 oxo acid is highly prone to oxygenation, giving a second 4-hydroperoxyalkenal, 8-hydroperoxy-11-oxoundeca-5,9-dienoic acid (not shown).