Editing 4-Hydroxynonenal (section)

==Detoxification and related reactions==
4-HNE has two reactive groups: the conjugated aldehyde and the C=C double-bond, and the hydroxy group at carbon 4.  The [[α,β-Unsaturated carbonyl compound|α,β-unsaturated ketone]] serves as a [[Michael acceptor]], adding thiols to give thioether adducts.

A small group of enzymes are specifically suited to the detoxification and removal of 4-HNE from cells.  Within this group are the [[glutathione S-transferase]]s (GSTs) such as hGSTA4-4 and hGST5.8, [[aldose reductase]], and [[aldehyde dehydrogenase]].  These enzymes have low [[Michaelis-Menten kinetics|K<sub>m</sub>]] values for HNE catalysis and together are very efficient at controlling the intracellular concentration, up to a critical threshold amount, at which these enzymes are overwhelmed and cell death is inevitable.

Glutathione S-transferases hGSTA4-4 and hGST5.8 catalyze the conjugation of [[glutathione]] peptides to 4-hydroxynonenal through a conjugate addition to the alpha-beta unsaturated carbonyl, forming a more water-soluble molecule, GS-HNE.  While there are other GSTs capable of this conjugation reaction (notably in the alpha class), these other isoforms are much less efficient and their production is not induced by the stress events which cause the formation of 4-HNE (such as exposure to [[hydrogen peroxide]], [[ultraviolet light]], [[heat shock]], cancer drugs, etc.), as the production of the more specific two isoforms is.  This result strongly suggests that hGSTA4-4 and hGST5.8 are specifically adapted by human cells for the purpose of detoxifying 4-HNE to abrogate the downstream effects which such a buildup would cause.

Increased activity of the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) has been shown to have a protective effect against [[cardiac ischemia]] in animal models, and the postulated mechanism given by the investigators was 4-hydroxynonenal metabolism.<ref>{{Cite journal | last1 = Chen | first1 = C. -H. | last2 = Budas | first2 = G. R. | last3 = Churchill | first3 = E. N. | last4 = Disatnik | first4 = M. -H. | last5 = Hurley | first5 = T. D. | last6 = Mochly-Rosen | first6 = D. | doi = 10.1126/science.1158554 | title = An Activator of Mutant and Wildtype Aldehyde Dehydrogenase Reduces Ischemic Damage to the Heart | journal = Science | volume = 321 | issue = 5895 | pages = 1493–1495 | year = 2008 | pmid =  18787169| pmc =2741612 }}</ref>