Lipid peroxidation and protein modification in a mouse model of chronic iron overload.
Iron-storage diseases are believed to cause organ damage through generation of reactive oxygen species. Using a murine model of iron overload, we found that hepatic iron stores increased logarithmically during 3 weeks of chronic intraperitoneal administration of iron dextran, while hepatic glutathione peroxidase activity declined linearly by approximately 50% during the same period. Plasma concentrations of aliphatic aldehydes increased by 2- to 3-fold, and plasma malondialdehyde (MDA) by 6-fold. Modification of total liver protein by products of lipid peroxidation, including MDA-lysine, 4-hydroxynonenal-lysine, and N(epsilon)-(carboxymethyl)lysine (CML), increased by approximately 3-fold, while levels of the protein oxidation marker, methionine sulfoxide (MetSO), were unchanged. Skin collagen was resistant to modification until the third week, when 2- to 3-fold increases in both CML and MetSO were observed. Our results document that iron overload increases lipid peroxidation, with concomitant increases in reactive aldehydes in plasma and chemical modification of tissue proteins. CML was a sensitive indicator of hepatocellular oxidative stress, compared to MetSO, while extensive modification of extracellular skin collagen was not observed until the late stages of iron overload and oxidative stress. These observations provide direct evidence for the contribution of reactive oxygen species, lipid peroxidation, and reactive carbonyl intermediates to the pathogenesis of iron-overload diseases.
Sochaski
Mark A
MA
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA.
Bartfay
Wally J
WJ
Thorpe
Suzanne R
SR
Baynes
John W
JW
Bartfay
Emma
E
Lehotay
Denis C
DC
Liu
Peter P
PP
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000139:chemically induced / Q000378:metabolism*; D007505:Iron-Dextran Complex / Q000008:administration & dosage; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009929:Organ Size; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism*; D012867:Skin / Q000737:chemistry
D000447:Aldehydes; D011506:Proteins; D008315:Malondialdehyde; D007505:Iron-Dextran Complex; D003094:Collagen; D007501:Iron