ENHANCED GAMMA-GLUTAMYL-TRANSPEPTIDASE EXPRESSION AND SELECTIVE LOSS OF CUZN SUPEROXIDE, DISMUTASE IN HEPATIC IRON OVERLOAD

Liver injury caused by iron overload is presumed to involve lipid pero xidation and the formation of products such as 4-hydroxynonenal (4HNE) , which has been implicated in hepatic fibrogenesis. Cellular antioxid ants that modulate the formation and detoxification of compounds such as 4HNE may represent important protective mechanisms involved in the response to iron overload, This study examines the relationship betwee n 4HNE, collagen content, and antioxidant defenses in the livers of ra ts fed carbonyl iron for 10 weeks. Iron-loading resulted in significan t increases in iron (8.8-fold), 4HNE(1.7-fold), and hydroxyproline (1. 5-fold). Total glutathione content was unchanged by iron, but gamma-gl utamyl transpeptidase activity (GGT) increased sixfold and CuZn supero xide dismutase (CuZnSOD) activity decreased >90%. GGT colocalized with iron deposition and was associated with increased GGT mRNA. Decreased CuZnSOD activity was paralleled by a reduction in CuZnSOD protein on Western blot and immunohistochemistry, but no decrease in CuZnSOD mRNA . Glutathione S-transferase (GST) and Mn superoxide dismutase (Mn SOD) activities were also significantly increased by iron loading. These r esults demonstrate that iron overload significantly alters the express ion of antioxidant enzymes associated with glutathione (GGT and GST) a nd superoxide metabolism (CuZnSOD and MnSOD). Furthermore, the localiz ed induction of GGT may enhance detoxification of lipid peroxidation-d erived aldehydes via glutathione-dependent pathways in iron-loaded hep atocytes. These alterations in antioxidant defenses may represent an a daptive response, limiting accumulation 4HNE, and thus, stimulation of collagen synthesis, accounting for the mild fibrogenic response seen in this model of iron overload. (C) 1998 Elsevier Science Inc.