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ToxSci Advance Access published online on December 1, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj054
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 29, 2005
Accepted November 22, 2005

In Vitro Toxicology

The Interaction of Arsine with Hemoglobin in Arsine-Induced Hemolysis

Leonard T. Rael 1 *, Felix Ayala-Fierro 2, Raphael Bar-Or 1, Dean E. Carter 3, and David S. Barber 4

1 Swedish Medical Center, Trauma Research Laboratory, Englewood, CO, USA 80113; DMI BioSciences, Inc., Englewood, CO, USA 80113
2 The Dial Corporation, Product Safety, Regulatory and Microbiology - Clinical Studies and Toxicology, Scottsdale, AZ, USA 85254
3 Department of Pharmacology and Toxicology, the Center for Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA 85721
4 Department of Physiological Sciences, Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, USA 32611

* To whom correspondence should be addressed.
Leonard T. Rael, E-mail: lrael{at}dmibio.com


  Abstract

The mechanism of arsine (AsH3) toxicity is not completely understood, but hemoglobin (Hb) has long been recognized as a necessary component to the overall mechanism of AsH3-induced hemolysis. In this study, the role of Hb in AsH3-induced hemolysis was investigated. The purpose was to determine whether exposure to AsH3 altered the structure of the heme or globin constituents of Hb. AsH3 was incubated with isolated, human oxyhemoglobin (oxyHb) and carboxyhemoglobin (carboxyHb), and the release of heme and formation of AsH3-induced hemoglobin modifications were examined. AsH3 increased the amount of heme released from oxyHb by 18%. When carboxyHb was incubated with AsH3, there was no change in heme release, suggesting that the sixth ligand position on the heme iron may be critical in the interaction with AsH3. AsH3-Hb interactions were studied by mass spectral analysis of heme, {alpha}-chain globin, and {beta}-chain globin. AsH3 had no significant effect on the {alpha}- or {beta}-chain LCMS spectra in oxyHb and carboxyHb, but in oxyHb, AsH3 consistently increased the frequency of methyl acetate ion fragment (•CH2OOH, m/z = 59) loss from heme in the MALDI-MS spectra. The formation of Hb-protein crosslinks was investigated by Western blotting using an anti-Hb antibody in isolated membranes from AsH3-treated erythrocytes, but no Hb-membrane adducts were found. These results suggest that the interaction between AsH3 and hemoglobin result in an increase in heme release which may contribute to the hemolytic mechanism of AsH3.

Keywords: arsine; oxyhemoglobin; carboxyhemoglobin; heme; hemolysis.
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