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CYTOTOXICITY AND CELLULAR RESPONSE TO a,~-UNSATURATED ALDEHYDES. ROLE OF ALDEHYDE DEHYDROGENASES Ngome Makia August 24, 2011 The lipid aldehydes, 4-hydroxy-2-nonenal (4-HNE) and propene-2-al (acrolein) are reactive a,~-unsaturated aldehydes generated during the peroxidation of lipids and are implicated in the pathogenesis of several oxidative-stress mediated diseases, including steatohepatitis and cancer. We established that mouse liver aldehyde dehydrogenase 1 al (Aldhlal) efficiently metabolizes lipid aldehydes and protects a liver-derived cell line from the toxic effects of these aldehydes. Thus, mechanisms to induce the expression of Aldhlal might be a useful rationale for preventing oxidative stress-induced pathologies. We investigate whether well-known electrophiles, such as BHA or acrolein modulate the expression of Aldhlal and elucidate the signaling pathway involved. Microarray analyses were performed to examine whether acrolein or BHA up-regulate the expression of genes encoding enzymes involved in antioxidant or electrophile detoxification in mice liver. Mice were administered AIN76A (control) diet, diet containing 0.45% BHA or 5 mg/kg acrolein by gavage for 7 days. The expression of genes encoding several electrophile detoxifying enzymes was specifically elevated, indicating a detoxification response. The elevation of Aldhlal was noticeable, with a 2to 3-fold increase by both electrophiles. Quantitative real-time peR analysis also showed ;::::2.5-fold and ;::::3-

Cytotoxicity and cellular response to alpha, beta-unsaturated aldehydes : role of aldehyde dehydrogenases.