A new role for Carbonyl Reductase 1 on 4-hydroxynonenal detoxification

4-Hydroxy-2-nonenal (HNE) is one of the main products of lipid autoxidation of unsaturated fatty acid (1). It is a highly reactive molecule and has received a particular attention for its biological activity and its role in different diseases (2). HNE metabolism is reported to mainly occur through its conjugation with glutathione and the subsequent formation of 3-glutathionyl-4-hydroxynonanal (GSHNE) (3). This molecule is susceptible to both reductive and oxidative transformations, which occur through the action of either the NADPH-dependent action of aldose reductase or the NADP+-dependent activity of aldehyde dehydrogenase, respectively. In this context it has been identified a role of carbonyl reductase 1 (CBR1) in the detoxification of GSHNE through its oxidation to the corresponding 3-glutathionyl-nonanoic-δ-lactone (4). More recently it has been also reported the capability of the enzyme to reduce GSHNE, together with a number of glutathionylated aldehydes, to the corresponding GS-dihydroxynonane (GSDHN) (5). Thus GSHNE, through its equilibrium between the open aldehyde form and its cyclic hemiacetal acts, with respect to CBR1, as a dual substrate. Being the two red/ox processes linked to the same red/ox cofactor (NADP+/NADPH), it turns out that a CBR1-catalyzed disproportion of GSHNE occurs. The high catalytic efficiency of CBR1 in the GSHNE processing, would suggest this molecule as one of the main physiological substrate of the enzyme. In this contest besides contributing to detoxification processes, CBR1 may be involved in the production of a signaling molecule, GSDHN, which is reported to activate inflammatory processes mediated by NFκB (6). These results could add new relevance on the inhibition of CBR1 activity by specific molecules that could play an anti-inflammatory role.