Protein adducts of malondialdehyde and 4-hydroxynonenal in livers of iron loaded rats: Quantitation and localization

M. Firoze Khan, Xiaohong Wu, Ulka R. Tipnis, G. A.S. Ansari, Paul J. Boor

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Pathophysiological mechanisms for hepatocellular injury, fibrosis and/or cirrhosis in hepatic iron overload are poorly understood. An increase in intracellular transit pool of iron can catalyze peroxidation of lipids to produce reactive aldehydes such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE). Covalent binding of such lipid aldehydes with proteins may cause impairment in cellular function and integrity. This investigation was focused on quantitative determination of MDA and HNE-protein adducts, and to establish a correlation between iron deposition and formation and localization of MDA and HNE-protein adducts, using immunohistochemistry. To achieve iron overload, male SD rats were fed a 2.5% carbonyl iron-supplemented diet for six weeks, while control animals received standard diet. Total iron as well as low molecular weight chelatable iron (LMWC-Fe) in the hepatic tissue of rats fed the iron supplemented diet increased significantly (∼14- and ∼15-fold, respectively). Quantitative ELISA for MDA-and HNE-protein adducts showed remarkable increases of 186 and 149%, respectively, in the liver homogenates of rats fed the iron-supplemented diet. Sections of liver stained for iron showed striking iron deposits in periportal (zone 1) hepatocytes, which was less dramatic in midzonal (zone 2) cells. Livers from iron-loaded rats showed strong, diffuse staining for both MDA and HNE adducts, which was highly pronounced in centrilobular (zone 3) hepatocytes, but was also evident in midzonal cells (zone 2). The demonstration of greater formation of both MDA and HNE-protein adducts provides evidence of iron-catalyzed lipid peroxidation in vivo. Although in this model of iron overload there was no evidence of tissue injury, our results provide an account of some of the initiating factors or early molecular events in hepatocellular damage that may lead to the pathological manifestations seen in chronic iron overload.

Original languageEnglish (US)
Pages (from-to)193-201
Number of pages9
JournalToxicology
Volume173
Issue number3
DOIs
StatePublished - May 1 2002

Keywords

  • 4-Hydroxynonenal
  • Immunohistochemistry
  • Iron overload
  • Lipid peroxidation
  • Liver
  • Malondialdehyde
  • Protein adducts

ASJC Scopus subject areas

  • Toxicology

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