Iron - Toxicology of Metals - page 581

body, and thence into various metalloproteins, is done
in a way that guards against the major danger of iron:
incidental metal-catalyzed oxidation reactions. Unfor-
tunately, mammals are not equipped with mechanisms
for the excretion of excess iron, and chronic iron over-
load is associated with slowly progressing failure of
various organs including heart, liver, and pancreas,
which in the absence of effective chelation therapy (in
secondary iron overload) or phlebotomy (in patients
with hereditary hemochromatosis) can bring on early
death. Similarly, acute overdose of large amounts of
medicinal iron is potentially life threatening. The mech-
anisms involved in this iron-mediated damage remain
incompletely understood, although iron-catalyzed oxi-
dation reactions are almost certainly at the core of the
disease process. An improved understanding of these
mechanisms may lead to the design of more effective
therapies for this devastating disorder.

Bacon, B. R., O'Neill, R. O., and Park, C. H. (1986). Free Rad. Biol. Med .
2, 339-347.
Bacon, B. R., Brittenham, G. M., Park, C. H., et al . (1988). Ann. N.Y.
Acad. Sci . 526, 155-163.
Bacon, B. R., O'Neill, R., and Britton, R. S. (1993). Gastroenterology
105, 1134-1140.
Balla, G., Vercellotti, G. M., Eaton, J. W., et al . (1990). J. Lab. Clin. Med .
116, 546-554.
Balla, G., Vercellotti, G. M., Eaton, J. W., et al . (1990). Trans. Assoc.
Amer. Phys . CIII, 174-179.
Balla, G., Vercellotti, G. M., Muller-Eberhard, U., et al . (1991). Lab.
Invest . 64, 648-655.
Balla, G., Jacob, H. S., Balla, J., et al . (1992). J. Biol. Chem . 267,
18148-18153.
Balla, J., Jacob, H. S., Balla, G., et al . (1993). Proc. Natl. Acad. Sci. USA
90, 285-289.
Banner, W., Jr., and Tong, T. G. (1986). Pediatr. Clin. North Am .
33, 393-409.
Bartfay, W. J., Butany, J., Lehotay, D. C., et al . (1999). Cardiovasc. Pathol .
8, 305-314.
Becker, E., and Richardson, D. R. (2001). Int. J. Biochem. Cell. Biol .
33, 1-10.
Becker, E. M., Greer, J. M., Ponka, P, et al . (2002). Blood 99, 3813-
3822.
Beckman, K. B., and Ames, B. N. (1998). J. Biol. Chem . 272, 19633-
19636.
Beckman, K. B., and Ames, B. N. (1998). Physiol. Rev . 78, 547-581.
Berlett, B. S., and Stadtman, E. R. (1997). J. Biol. Chem . 272,
20313-20316.
Bezkorovainy, A. (1989a). Clin. Physiol. Biochem . 7, 1-17.
Bezkorovainy, A. (1989b). Clin. Physiol. Biochem . 7, 53-69.
Bielski, B. H. (1992). Ann. Neurol . 32, S28-S32.
Bomford, A., Isaac, J., Roberts, S., et al . (1986). Biochem. J ., 236, 243-249.
Bothwell, T. H., Seftel, H., Jacobs, P., et al . (1964). Am. J. Clin. Nutr .
14, 47-51.
Bradbear, R. A., Bain, C., Siskind, V., et al . (1985). J. Natl. Cancer Inst .
75, 81-84.
Britton, R. S., Ramm, G. A., Olynyk, J., et al . (1994). Adv. Exp. Med.
Biol . 356, 239-253.
Brown, K. E., Kinter, M. T., Oberley, T. D., et al . (1998). Free Radic. Biol.
Med . 24, 545-555.
Brunk, U. T., Neuzil, J., and Eaton, J. W. (2001). Redox Report 6,
91-97.
Camaschella, C., Roetto, A., Cali, A., et al . (2000). Nat. Genet . 25,
14-15.
Canonne-Hergaux, F., Gruenheid, S., Ponka, P., et al . (1999). Blood 93,
4406-4417.
Canonne-Hergaux, F., Zhang, A. S., Ponka, P., et al . (2001). Blood 98,
3823-3830.
Carmichael, P. L., Hewer, A., Osborne, M. R., et al . (1995). Mutat. Res .
326, 253-243.
Cazzola, M., Invernizzi, R., Bergamaschi, G., et al . (2003). Blood 101,
1996-2000.
Cellier, M., Prive, G., Belouchi, A., et al . (1995). Proc. Natl. Acad. Sci.
USA 92, 10089-10093.
Chance, B., Sies, H., and Boveris, A. (1979). Physiol. Rev . 59, 527-605.
Chen, O. S., Hemenway, S., and Kaplan, J. (2002). Proc. Natl. Acad. Sci.
USA 99, 12321-12326.
Chen, Z., Griffi n, I. J., Plumlee, L. M., et al . (2005). J. Nutr . 135, 1790-
1795.
Cheng, Y., Zak, O., Aisen, P., et al . (2004). Cell 116, 483-485.
Cook, C. I., and Yu, B. P. (1998). Mech. Ageing Dev . 102, 1-13.
Cooperman, S. S., Meyron-Holtz, E. G., Olivierre-Wilson, H., et al .
(2005). Blood 106, 1084-1091.

Acknowledgments
This work was supported in part by the Canadian Institutes
of Health Research (P.P.) and the NIH (DK58882), the Ken-
tucky Lung Cancer Research Program, the Philip Morris Exter-
nal Research Program, and the Commonwealth of Kentucky
Research Challenge Trust Fund (J.W.E.). The authors thank
Mrs. Miriam Rosenzweig for assistance; Professor Willem Kop-
penol for helpful comments; and members of their laboratories
for many intellectual contributions.

References

Abboud, S., and Hailey, D. J. (2000). J. Biol. Chem . 275, 19906-19912.
Adams, P. C. (2004). Clin. Liver Dis . 8, 735-753.
Aisen, P., Enns, C., and Wessling-Resnick, M. (2001). Int. J. Biochem.
Cell Biol . 33, 940-59.
Aisen, P. (2004). Int. J. Biochem. Cell Biol . 36, 2137-2143.
Aldouri, M. A., Wanke, B., and Hoffbrand, A.V. (1990). Acta. Haema-
tol . 84, 113-117.
Alikments, R., Raskind, W. H., Hutchinson, A., et al . (1999). Hum.
Mol. Genet . 8, 743-749.
Altman, S. A., Satawany, T. H., Randers-Eichhorn, L., et al . (1995).
Free Radic. Biol. Med . 19, 897-902.
Anderson, G. J., Frazer, D. M., McKie, A. T., et al . (2002). Blood Cells
Mol. Dis . 29, 367-375.
Andrews, N. C. (2005). Best Pract. Res. Clin. Haematol . 18, 159-169.
Arouma, O. I., Bomford, A., Polson, R. J., et al . (1988). Blood ,
72, 1416-1419.
Artiss, J. D., Vingradov, S., and Zak, B. (1981). Clin. Biochem .
14, 311-315.
Babcock, M., de Silva, D., Oaks, R., et al . (1997). Science 276,
1709-1712.
Bacon, B. R., Brittenham, G. M., Tavill, A. S., et al . (1983). Trans. Assoc.
Am. Phys . 96, 146-154.
Bacon, B. R., Tavill, A. S., Brittenham, G. M., et al . (1983). J. Clin. In-
vest . 71, 429-438.
Bacon, B. R., Park, C. H., Brittenham, G. M., et al . (1985). Hepatology
5, 789-797.