title: Oxidative stress response in iron-induced renal carcinogenesis: acute nephrotoxicity mediates the enhanced expression of glutathione S-transferase Yp isozyme.
abstract: An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces acute renal proximal tubular necrosis, a consequence of free radical-mediated oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we investigated the free radical-induced oxidative stress response in this carcinogenesis model, focusing on the expression of glutathione S-transferases (GSTs) which catalyze the conjugation of reactive chemicals with glutathione and play an important role in protecting cells. A single intraperitoneal Fe-NTA treatment (15 mg Fe/kg body weight) induced a rapid oxidative stress, which was monitored by the accumulation of lipid peroxidation products and the loss of sulfhydryl contents in the kidneys, resulting in a 30% reduction of GST activity 1 h after an Fe-NTA treatment. The enzyme activity returned to the control level after 16 h. The immunoblot analysis of GST isozymes demonstrated that the level of alpha-class GSTs (GST-Ya and GST-Yc) and pi-class GST (GST-Yp), major GST isozymes constitutively produced in the kidney, decreased immediately within 1 h of the Fe-NTA treatment. The onset of the recovery of GST-Yp protein levels was detected 3 h after the Fe-NTA treatment. The enhanced production of GST-Yp in gene expression was evident in the drastic elevation of mRNA levels and these increases coincided with a substantial rise in the GST activity and protein levels. The alpha-class GSTs were not inducible by treatment with Fe-NTA. The immunohistochemical analysis demonstrated that the expression of GST-Yp was strongly induced in the regenerating proximal tubular cells. A steady accumulation of GST-Yp protein was observed in the subacute toxicity experiments with multiple injections of Fe-NTA. These results suggest that the enhanced expression of GST-Yp is important in mediating cell repairs or increasing the resistance to subsequent injury.
authors.affiliation: Laboratory of Food and Biodynamics, Nagoya University School of Agriculture, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Fukuda
authors.forename: T
authors.initials: T
authors.lastname: Osawa
authors.forename: H
authors.initials: H
authors.lastname: Oda
authors.forename: S
authors.initials: S
authors.lastname: Toyokuni
authors.forename: K
authors.initials: K
authors.lastname: Satoh
authors.forename: K
authors.initials: K
authors.lastname: Uchida
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D005290:Ferric Compounds / Q000633:toxicity*; D005609:Free Radicals / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000096:biosynthesis*; D007502:Iron Chelating Agents / Q000633:toxicity*; D007527:Isoenzymes / Q000096:biosynthesis*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002273:Carcinogens; D005290:Ferric Compounds; D005609:Free Radicals; D007502:Iron Chelating Agents; D007527:Isoenzymes; D005982:Glutathione Transferase; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate