Identification of metabolic pathways of the lipid peroxidation product 4-hydroxynonenal in in situ perfused rat kidney

Abstract

The metabolism of the cytotoxic lipid peroxidation product 4-hydroxynonenal was studied in perfused rat kidney. We investigated the total capacity of the rat kidney to metabolize 4-hydroxynonenal (HNE) and quantified the metabolites in the venous effluents as well as in the excreted urine. A rapid utilization of HNE was demonstrated, due to its immediate reactions with cellular compounds and its metabolism. During the first 3 min more than 80% of the infused HNE was metabolized in the perfused kidney. Glutathione-HNE conjugate (GSH-HNE: 35%), the corresponding alcohol 1,4-dihydroxynonene (1,4-DHN: 12%), HNE-mercapturic acid conjugate (HNE-MA: 4%), 4-hydroxynonenoic acid (HNA: 7%), tricarboxylic acid (TCA-cycle metabolites), and water (32%) were identified as primary and secondary metabolic products. We postulated that the total capacity of rat kidney to metabolize 4-hydroxynonenal with about 160-190 nmol/g wet wt/min. (initial influent concentration was 100 nmol/ml HNE) and other aldehydic products of lipid peroxidation is in the same range as that in other organs, e.g., intestine with 22 nmol/g wet wt/min (initial 70 nmol/ml HNE) (Siems et al. 1995. Life Sci. 57: 785-789) and heart with about 50 nmol/g wet wt/min (initial 10 nmol/ml HNE) (Grune et al. 1994. Cell Biochem. Funct. 12: 143-147). Compared to other organs, liver and kidney seemed to be the most important organs for the elimination of the final products of metabolism. The importance of the kidney in the formation of HNE-mercapturic acid conjugate was demonstrated (Alary et al. 1995. Chem. Res Toxicol. 8: 34-39). The selective excretion of this final metabolite of aldehyde metabolism may be of central importance in the detoxification of a number of lipid peroxidation products.