Iron chelation as a possible mechanism for aspirin-induced malondialdehyde production by mouse liver microsomes and mitochondria.
To investigate the possibility that lipid peroxidation is the mechanism responsible for aspirin-induced liver damage, pure neutralized acetylsalicylic acid (ASA), 0.6-90.9 mM, was added to calcium-aggregated mouse liver microsomes followed by incubation in NADPH buffer at 37 degrees C for 60 min and subsequent measurement of malondialdehyde (MDA). MDA production at ASA concentrations from 1.2 to 4.6 mM was greater than control (P less than 0.004). Peak MDA values were observed with 4.6 mM ASA, 39.58 +/- 6.73 nmol MDA/mg protein vs. 16.16 +/- 2.85 (P less than 0.004). Higher concentrations of ASA were inhibitory compared with the value at 4.6 mM (P less than 0.001). Aspirin had similar effects on MDA production by mouse liver mitochondria. MDA production with either ASA or buffer was completely suppressed by the potent iron-chelating agents desferrioxamine and alpha,alpha' dipyridyl when these were added to the microsomal preparations. Since MDA production in this system is known to be affected by iron-chelating agents (enhanced at low concentration, inhibited at higher concentration), the iron-chelating properties of ASA were investigated. Conductivity titration curves of Fe(OH)3 added to water or ASA suggested that the ASA was complexing with iron. The presence of an iron-ASA complex was established by high pressure liquid chromatographic analysis of the solution from this study. We conclude that aspirin enhances MDA production by hepatic microsomes and mitochondria via an aspirin-iron chelate and that this represents at least one mechanism by which aspirin may produce liver damage.
Schwarz
K B
KB
Department of Pediatrics, St. Louis University School of Medicine, Missouri.
Arey
B J
BJ
Tolman
K
K
Mahanty
S
S
D000818:Animals; D001241:Aspirin / Q000633:toxicity*; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000096:biosynthesis*; D008315:Malondialdehyde / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*
D007502:Iron Chelating Agents; D008054:Lipid Peroxides; D008314:Malonates; D008315:Malondialdehyde; D003676:Deferoxamine; D001241:Aspirin