Differential effects of iron overload on GST isoform expression in mouse liver and kidney and correlation between GSTA4 induction and overproduction of free radicles.
We have investigated the effect of iron overload on the expression of mouse GSTA1, A4, M1, and P1 in liver, the main iron storage site during iron overload, and in kidney. In iron-overloaded animals, mRNA and protein levels of GSTA1, A4, and M1 were increased in liver. In kidney, GSTA4 protein level was also increased while, unexpectedly, GSTA1 and M1 expression was strongly decreased. We showed, by immunohistochemistry, that GSTA4 was more abundant in hepatocytes of periportal areas and in convoluted proximal tubular cells in normal liver and kidney, respectively. In iron-overloaded mice, GSTA4 staining was more intense in cells that preferentially accumulated iron, and conjugation of 4-hydroxynonenal, a specific substrate of GSTA4, was enhanced in both organs. Moreover an acute exposure of primary cultures of mouse hepatocytes to iron-citrate strongly induced oxidative stress and cellular injury and resulted in an increase in GSTA4 expression, while cotreatment with iron-citrate and either desferrioxamine or vitamin E prevented both toxicity and GSTA4 induction. These data demonstrate that GSTA1 and M1 are differentially regulated in liver and kidney while GSTA4 is induced in both organs during iron overload. Moreover, they support the view that iron-induction of GSTA4 is related to an overproduction of free radicals.
Desmots
Fabienne
F
INSERM U456, Faculté de Pharmacie, Université de Rennes I, 2 Avenue du Pr. Léon Bernard, 35043 Rennes Cedex, France.
Rissel
Mary
M
Pigeon
Christelle
C
Loyer
Pascal
P
Loréal
Olivier
O
Guillouzo
André
A
D000818:Animals; D004790:Enzyme Induction; D005609:Free Radicals / Q000378:metabolism*; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007501:Iron / Q000008:administration & dosage; D019190:Iron Overload / Q000201:enzymology / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000819:agonists / Q000235:genetics
D005609:Free Radicals; D012333:RNA, Messenger; D007501:Iron; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase