Iron-induced oxidant stress in nonparenchymal liver cells: mitochondrial derangement and fibrosis in acutely iron-dosed gerbils and its prevention by silybin.
Hepatic fibrosis due to iron overload is mediated by oxidant stress. The basic mechanisms underlying this process in vivo are still little understood. Acutely iron-dosed gerbils were assayed for lobular accumulation of hepatic lipid peroxidation by-products, oxidant-stress gene response, mitochondrial energy-dependent functions, and fibrogenesis. Iron overload in nonparenchymal cells caused an activation of hepatic stellate cells and fibrogenesis. Oxidant-stress gene response and accumulation of malondialdehyde-protein adducts were restricted to iron-filled nonparenchymal cells, sparing nearby hepatocytes. Concomitantly, a significant rise in the mitochondrial desferrioxamine-chelatable iron pool associated with the impairment of mitochondrial oxidative metabolism and the hepatic ATP decrease, was detected. Ultrastructural mitochondrial alterations were observed only in nonparenchymal cells. All biochemical and functional derangements were hindered by in vivo silybin administration which blocked completely fibrogenesis. Iron-induced oxidant stress in nonparenchymal cells appeared to bring about irreversible mitochondrial derangement associated with the onset of hepatic fibrosis.
Pietrangelo
Antonello
A
Dipartimento di Medicina Interna e Sezione di Patologia Generale, Università di Modena, Italy. pietra@unimo.it
Montosi
Giuliana
G
Garuti
Cinzia
C
Contri
Miranda
M
Giovannini
Fabiola
F
Ceccarelli
Daniela
D
Masini
Alberto
A
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D005849:Gerbillinae; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007501:Iron / Q000008:administration & dosage / Q000633:toxicity*; D019190:Iron Overload / Q000150:complications / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D012838:Silymarin / Q000494:pharmacology / Q000627:therapeutic use
D012838:Silymarin; D000255:Adenosine Triphosphate; D007501:Iron; D003576:Electron Transport Complex IV