Involvement of Human Carbonyl Reductase 1 in the metabolism of glutathionylated lipid aldehydes metabolism

4-hydroxynonenal (HNE) is one of the most abundant lipid peroxidation products and it is involved in the development of several pathological conditions. As other unsaturated lipid aldehydes, HNE readily reacts with glutathione, thus giving rise to the formation of 3-glutathionyl-4-hydroxynonanal (GSHNE). This step makes the removal of GSHNE, and in general of the glutathione-aldehydes adducts, a relevant pathway in lipid aldehydes detoxification. Human carbonyl reductase 1 (hCBR1), a member of the short chain dehydrogenase family, catalyses the reduction of glutathionylated aldehydes with an efficiency comparable to that observed for classical hCBR1 substrates. In the case of GSHNE, two functional groups are recognized by the catalytic action of hCBR1. In fact, the enzyme is able to both reduce the aldehydic group generating 3-glutathionyl-dihydroxynonane (GSDHN) and oxidize the hemiacetalic form generating 3-glutathionylnonanoic-γ-lactone. This disproportion reaction is supported by the recycle of the cofactor NADP+. Thus, hCBR1 may play a role in HNE detoxification, at the same time contributing to the recovery of reducing power. Moreover, the possibility to generate GSDHN, a signaling molecule that activates NFkB, makes hCBR1 possibly involved in the inflammation response.