New hypotheses on the pathways of formation of malondialdehyde and isofurans.

Malondialdehyde (MDA) is a mutagenic compound that has been widely used as a biomarker of oxidative stress. However, the nonenzymatic mechanisms of its formation are not well understood. Some lipid oxidation products were previously suggested to be MDA precursors and found to afford MDA heterolytically under acidic conditions. We predict that some of these compounds are not important MDA sources under the autoxidative conditions under which the bulk of MDA should be formed in vivo and that others require further oxidative modifications to generate MDA homolytically. Thus, we outline the likely important pathways of MDA formation in vivo. All these pathways are intense aldehyde producers, generating two other aldehydic products for every MDA molecule formed. Some of the predicted aldehydes are new and may merit further analytical and biological studies. Peracids derived from the aldehydes are proposed to participate in the formation of isofurans (which at high oxygen tensions are excellent markers of oxidative stress) as well as important bioactive epoxides such as leukotoxins. This generates interest in the biological relevance of lipid aldehyde-derived peracids. The suitability of tissue MDA determination methods is discussed based on their likelihood of involving acid-catalyzed artifactual MDA formation.