SEX-DIFFERENCES IN OXIDATIVE DAMAGE IN DDY MOUSE KIDNEY TREATED WITH A RENAL CARCINOGEN, IRON NITRILOTRIACETATE

sIron-induced free radical injuries in male and female ddY mice, espec ially the sex difference and its mechanisms, were studied after an i.p . injection of a renal carcinogen, ferric nitrilotriacetate. Male mice were much more susceptible to iron-induced free radical injuries than female mice, Oxidative modification of proteins and DNA occurred more strongly in males than in females, as measured by protein carbonyl co ntent and 8-hydroxydeoxy-guanosine, respectively. Histochemical detect ion of 4-hydroxy-2-nonenal-modified proteins using an antibody and DNA fragmentation as detected by the TUNEL method also showed that males are more severely damaged than females, especially in the proximal con voluted tubules, These results could not be explained by the differenc e in iron status between male and female mice. In fact, the toxic so-c alled 'free' iron in serum and kidney were not different between male and female mice and storage iron, such as ferritin and hemosiderin, wa s also comparable in both kidneys. In previous studies we proposed the glutathione cycling hypothesis to explain the sex differences. The ha lf-life of glutathione in the kidney was significantly shorter in male s (29 min) than in females (57 min), as determined by the glutathione decrease after buthionine sulfoximine treatment, a specific inhibitor of glutathione synthesis. The specific activity of gamma-glutamyltrans peptidase (EC 2.3.2.2) in female mice was 73% of that in male mice. Th ese results suggest that the faster glutathione turnover in males coul d account for the higher susceptibility to oxidative injury by supplyi ng the reducing equivalent that reduces Fe(III) to Fe(II), thereby fac ilitating iron-catalyzed free radical reactions.