Metabolism of salicylate by isolated kidney and liver mitochondria.
Mitochondria are known to contain a P-450 like system similar to that found in microsomes. Since previous in vivo studies from this laboratory have suggested that renal mitochondria may metabolize salicylate (SAL) to a reactive intermediate capable of protein binding, the ability of isolated kidney and liver mitochondria to activate salicylate was investigated. Renal mitochondria were 4 times more active than liver in converting SAL to a reactive intermediate and metabolized approx. 1% of the SAL to 2,3-dihydroxybenzoic acid, the catechol analogue of SAL. The formation of 2,3-dihydroxybenzoate (2,3-DHBA) and the amount of radiolabel bound to mitochondrial protein was decreased in the presence of SKF 525-A; however, excess unlabeled metabolite had no effect on binding. These data indicate that kidney mitochondria activate SAL via a cytochrome P-450 like system, but suggest that the binding species is not 2,3-DHBA itself. Oxidation of SAL and covalent binding of radiolabel, however, were also observed after the addition of ferrous iron and ascorbic acid to a model system containing [14C]SAL and bovine serum albumin. Mannitol decreased SAL oxidation and covalent binding, suggesting radical formation may represent a non-enzymatic mechanism for SAL activation.
D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D002855:Chromatography, Thin Layer; D005296:Ferrous Compounds / Q000378:metabolism; D005841:Gentisates; D062385:Hydroxybenzoates / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D011335:Proadifen / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012459:Salicylates / Q000378:metabolism*; D020156:Salicylic Acid
D005296:Ferrous Compounds; D005841:Gentisates; D062385:Hydroxybenzoates; D012459:Salicylates; C020748:ferrous sulfate; D008353:Mannitol; D011335:Proadifen; D020156:Salicylic Acid; D001205:Ascorbic Acid; C010925:2,5-dihydroxybenzoic acid