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The iron chelator deferoxamine has been reported to inhibit both xanthine oxidase (XO) and xanthine dehydrogenase activity, but the relationship of this effect to the availability of iron in the cellular and tissue environment remains unexplored. XO and total xanthine oxidoreductase activity in cultured V79 cells was increased with exposure to ferric ammonium sulfate and inhibited by deferoxamine. Lung XO and total xanthine oxidoreductase activities were reduced in rats fed an iron-depleted diet and increased in rats supplemented with iron, without change in the ratio of XO to total oxidoreductase. Intratracheal injection of an iron salt or silica-iron, but not aluminum salts or silica-zinc, significantly increased rat lung XO and total xanthine oxidoreductase activities, immunoreactive xanthine oxidoreductase, and the concentration of urate in bronchoalveolar fluid. These results suggest the possibility that the production of uric acid, a major chelator of iron in extracellular fluid, is directly influenced by iron-mediated regulation of the expression and/or activity of its enzymatic source, xanthine oxidase. xanthine dehydrogenase; deferoxamine; silica; uric acid

An experiment was conducted to determine whether H2O2 influences the activity produced by mammalian intrinsic cardiac neurons and whether the Fe2+ chelator deferoxamine inhibits H2O2-induced intrinsic cardiac neuronal effects as it has been shown to do with respect to cardiac afferent neurons. Data indicate, among other things, that locally released H2O2 affects a population of intrinsic cardiac neurons in situ by Fe2+-dependent generation of .OH- radicals.

The iron chelator desferrioxamine, Desferal, inhibits the production of both superoxide anion and hydrogen peroxide by the red tide phytoplankton Chattonella marina in a concentration-dependent way. The growth of C. marina is also inhibited by Desferal. Normally, superoxide anion production in C. marina is the greatest during the exponential growth phase, however, no such increase is observable in C. marina growing in an iron-deficient medium. The results indicate that iron is essential for the production of activated oxygen species by C. marina and its own growth.

The role of low-density lipoproteins (LDL) in promoting tubulointerstitial disease and renal cytotoxicity was analyzed in patients with proteinuric renal disease. Oxidized LDL contribute to tubulointerstitial disease by causing cytotoxicity in the renal tubular epithelium and endothelial cells. However, the cytotoxic effects of LDl was inhibited by alpha-tocopherol, ascorbic acid, butylated hydroxytoluene and deferoxamine.

A study using the L6 line of skeletal muscle cells was conducted to determine the effect of the iron chelators deferoxamine and bipyridyl on glucose transport and the expression of the GLUT-1 transmembrane glycoprotein in cultured muscle cells. The results show that L6 muscle cells responded to the reduction of iron availability due to iron chelators by enhancing GLUT-1 expression, which increased glucose transport. Furthermore, muscle cells adapted to reduced iron availability without losing their normal sensitivity to insulin.

Cell killing, inhibitor-insensitive oxygen consumption and hydroperoxide formation were observed in rat hepatocytes after glycolysis and respiration were inhibited. Observations demonstrated that reactive oxygen species take active roles in cell killing during chemical hypoxia. Past studies indicate that myxothiazol reduces Q-cycle mediated ubisemiquinone formation which can react with molecules of oxygen to form superoxide. Decreased hepatocyte killing with myxothizol suggest that oxygen radical formation by complex III in mitochondria is involved in cell killing during hypoxia.

Bacterial infection with Yersinia enterocolitica is characterized by gastrointestinal symptoms such as diarrhea and abdominal pain, and systemic symptoms such as fever. In most cases this infection is self-limiting, and does not present a severe health hazard. However, in patients with underlying disease such as diabetes, liver disorders, alcoholism, or disorders of iron metabolism, the prognosis can be much worse. A quite rare (eight reported cases) complication of YE infection is intestinal perforation, which occurs when the wall of the intestine loses its structural integrity, allowing the contents of the gastrointestinal tract to spill out into the abdominal cavity. This development can be fatal. A case is described of a 17-year-old white male who was admitted to the hospital complaining of abdominal pain and diarrhea of 10 days' duration. He was known to have beta-thalassemia intermedia (a disorder of iron metabolism), and had been treated for five years with blood transfusions, folic acid, vitamin C, and deferoxamine (a drug that removes iron from the blood). Abdominal pain, especially in the lower right quadrant, was notable. Based on tests done after admission, a preliminary diagnosis of appendicitis was made, and surgery was performed. At that time, the intestinal perforation was noted and recognized as the actual cause of his distress, and the afflicted segment was removed. In addition, nodules of various sizes were noted on and embedded in the liver. Tissue samples were taken for analysis, and YE was later identified in tissue culture. The patient was treated with antibiotics (amikacin and ampicillin) and was discharged 30 days after admission, having made a full recovery. (Consumer Summary produced by Reliance Medical Information, Inc.)

Liang, Mingyu, Anthony J. Croatt, and Karl A. Nath. Mechanisms underlying induction of heme oxygenase-1 by nitric oxide in renal tubular epithelial cells. Am J Physiol Renal Physiol 279: F728-F735, 2000.--We examined whether nitric oxide-generating agents influence expression of heme oxygenase-1 (HO-1) in renal proximal tubular epithelial cells, LLC-[PK.sub.1] cells, and the mechanisms underlying any such effects. In sublytic amounts, the nitric oxide donor sodium nitroprusside induced HO-1 mRNA and protein and HO activity in a dose-dependent and time-dependent fashion; this induction was specific for nitric oxide since the nitric oxide scavenger carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline -1-oxyl-3-oxide significantly reduced such induction. The induction of HO activity by sodium nitroprusside, or by another nitric oxide donor, spermine NONOate, was markedly reduced by the iron chelator deferoxamine. Two different thiol-containing agents, N-acetylcysteine and dithiothreitol, blunted such induction of HO by nitric oxide. Downstream products of nitric oxide, such as peroxynitrite or cGMP, were not involved in inducing HO. In higher concentrations (millimolar amounts), sodium nitroprusside induced appreciable cytotoxicity as assessed by lactate dehydrogenase (LDH) release and lipid peroxidation, and both of these effects were markedly reduced by deferoxamine. Inhibition of HO did not affect the cytotoxic effects (measured by LDH release) of sodium nitroprusside. We thus provide the novel description of the induction of HO-1 in renal proximal tubular epithelial cells exposed to nitric oxide donors and provide the first demonstration in kidney-derived cells for the involvement of a redox-based mechanism in such expression. We also demonstrate that, in LLC-[PK.sub.1] cells exposed to nitric oxide donors, chelatable iron is involved in eliciting the HO-1 response observed at lower concentrations of these donors, and in mediating the cytotoxic effects of these donors when present in higher concentrations. cell injury; oxidant stress; kidney; deferoxamine

Transcriptional regulation of heme oxygenases by HIF-1[alpha] in renal medullary interstitial cells. Am J Physiol Renal Physiol 281: F900-F908, 2001.--The present study was designed to test the hypothesis that hypoxia-inducible factor-1[alpha] (HIF-1[alpha])-mediated transcriptional activation contributes to increased expression of heme oxygenase (HO) genes in renal medullary interstitial cells (RMICs). By Northern blot analysis, HO-1 mRNA expression was found to significantly increase in response to reduction of P[O.sub.2] in culture medium. However, HO-2 mRNA was not altered by hypoxia. This hypoxia-induced upregulation of HO-1 mRNA was significantly blocked by HIF-1[alpha] inhibition with ferrous ammonium sulfate. To further determine the role of HIF-1[alpha] in the activation of HO-1, the inducers of HIF-1[alpha] were used to address whether induction of HIF-1[alpha] stimulates HO-1 mRNA expression. Both desferrioxamine and Co[Cl.sub.2] markedly increased HIF-1[alpha] mRNA and protein levels and resulted in the upregulation of HO-1 mRNA but not HO-2. Furthermore, inhibition of HIF-1[alpha] degradation by CBZ-LLL, an inhibitor of ubiquitin-proteasome, significantly increased HIF-1[alpha] protein and HO-1 mRNA but not HO-2 in these cells. Using cis-element oligode-oxynucleotide transfection to specifically decoy HIF-1[alpha] and block HIF-1[alpha] binding, increased mRNA expression of HO-1 in response to hypoxia and Co[Cl.sub.2] was attenuated. In vitro nuclear run-on assays further confirmed that hypoxia and alterations of HIF-1[alpha] mRNA or protein levels significantly affected the formation of HO-1 mRNA. Taken together, our results indicate that HO-1, but not HO-2, is transcriptionally activated by hypoxia through HIF-1[alpha]-mediated mechanism in RMICs. This hypoxia-induced transcriptional activation may be one of the important mechanisms mediating increased expression of HO-1 in the renal medulla. hypoxia-inducible factor-1[alpha]; gene transcription; anoxia