Molecular Pharmacology, Vol 3, 378-385, Copyright © 1967 by the American Society for Pharmacology and Experimental Therapeutics

The Oxygen and Sulfide Binding Characteristics of Hemoglobins Generated from Methemoglobin by Two Erythrocytic Systems

¹ Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755

Methemoglobinemia induced in mice and other animals protects against death from inhaled hydrogen sulfide or injected sodium sulfide. Equivalent circulating levels of methemoglobin impart equivalent degrees of protection irrespective of the agent used to induce the methemoglobinemia (nitrite, p-aminopropiophenone, or hydroxylamine). In each case 2-4 moles of sulfide are apparently inactivated in vivo for each available ferric heme group. The ferric iron of methemoglobin is one site available for hydrosulfide anion binding. No information is available about the nature of the additional sulfide binding sites, but they are inferred to be associated with the globin moiety.

Protection against sulfide poisoning is not demonstrable in mice after methemoglobin levels have been reduced to normal concentrations by spontaneous methemoglobin reductase activity. However, if methemoglobin reductase activity is increased by methylene blue, a ferrous hemoglobin which retains significant sulfide-inactivating properties exists transiently in vivo. This protective effect is also lost after a time interval equivalent to that required for spontaneous activity to reduce methemoglobin levels to normal in the absence of methylene blue. In mouse erythrocytes exposed to sodium nitrite the nonmethemoglobin heme produced as a result of methylene blue-induced reductase activity has only one-tenth of the oxygen capacity of normal mouse hemoglobin or the product of normal mouse methemoglobin reductase activity. A fully functional mouse hemoglobin in terms of its oxygen capacity is eventually generated in the presence of both methylene blue and nitrite if enough time is allowed for the spontaneous reductase to act. Similarly, the total ferrous hemoglobin products of methylene blue-induced reductase activity in nitrited human cells have less than half the oxygen-binding capacity of normal human hemoglobin. These findings suggest that spontaneous reductase activity restores a fully functional hemoglobin whereas methylene blue-induced reductase activity only reduces the heme iron. The methylene blue therapy of methemoglobinemia bears reexamination in terms of these findings.

Note:
ACKNOWLEDGMENTS These studies were supported in part by Research Grant AP 00260, Division of Air Pollution, USPHS. We are grateful to Professor G. E. Likens, Department of Biological Sciences, Dartmouth College, for allowing us use of his atomic absorption spectrophotometer. Mrs. Jean Williams assisted in many of these experiments.

This article has been cited by other articles:

				A. J. ARP and J. J. CHILDRESS Sulfide Binding by the Blood of the Hydrothermal Vent Tube Worm Riftia pachyptila Science, January 21, 1983; 219(4582): 295 - 297. [Abstract] [PDF]