A Study of Some of the Physiological Effects of Sulfanilamide. Ii. Methemoglobin Formation and Its Control

Hartmann, Alexis F.; Perley, Anne M.; Barnett, Henry L.

doi:10.1172/jci100997

Cited by 54 publications

(11 citation statements)

References 9 publications

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“…We have confirmed this photochemical change of sulfanilamide. The results of our investigation are in agreement with those of Hartmann and his associates who showed that the cyanosis was related to methemoglobin formation and that methylene blue administered to cyanotic patients caused a disappearance of the cyanosis and a reduction in the concentration of methemoglobin (4).…”

supporting

confidence: 93%

The Relation of Methemoglobin to the Cyanosis Observed After Sulfanilamide Administration

Vigness¹,

Watson²,

Spink³

1940

J. Clin. Invest.

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We have stated in a preliminary report that the cyanosis observed in individuals treated with sulfanilamide is due to methemoglobin, and rarely, to sulfhemoglobin (1). We recognized at the time that attempts had been made to explain the presence of cyanosis on a different basis.. Marshall and Walzl (2) maintained that a black pigment derived from sulfanilamide, and present in the blood, was the cause of this cyanosis. A similar explanation was advanced by Ottenberg and Fox (3). They described the phenomenon of a bluish-purple pigment resulting when a colorless sulfanilamide solution was exposed to ultra violet light. We have confirmed this photochemical change of sulfanilamide. The results of our investigation are in agreement with those of Hartmann and his associates who showed that the cyanosis was related to methemoglobin formation and that methylene blue administered to cyanotic patients caused a disappearance of the cyanosis and a reduction in the concentration of methemoglobin (4).At this time we desire to present further evidence that the cyanosis is due solely to the presence of methemoglobin, and in rare instances, to sulfhemoglobin. We have also included the results of a study of individuals receiving sulfapyridine. Spectral distribution curves were obtained with the spectrophotometer, using normal human blood and the bloods of patients to whom sulfanilamide or sulfapyridine was being administered. In initiating such a study, we believed that if any pigment other than methemoglobin that might cause cyanosis were present, it would be detected in the spectral distribution curves. MATERIAL AND METHODSSpectroscopic studies have been carried out on the bloods of 3 normal adults, 15 patients receiving sulfanilamide, and 5 more to whom sulfapyridine was given. From 4 to 8 grams of sulfanilamide were administered to the patients daily in divided doses for several days because of the presence of an infection. The free sulfanilamide in their bloods was determined on the day the bloods were examined for methemoglobin. These levels ranged from 4.9 to 20.8 mgm. of sulfanilamide per 100 cc. of blood. Sulfapyridine was given in divided doses for a total of 4 to 9 grams per day. The blood levels of free sulfapyridine varied from 2 to 14 mgm. per 100 cc. of blood. Data for the absorption curves were obtained with a Marten's type polarization photometer in combination with a Bausch and Lomb spectrometer. The spectrophotometric examinations were made in the range from 480 to 700 m/A. Whole blood was diluted with distilled water to give a concentration of 1: 25 or 1: 50. This solution was centrifuged for 10 minutes at 2400 revolutions per minute (radius 10 inches) in order to remove the stroma of the cells and clarify the solution. Absorption cells 0.5 or 1.0 cm. in length were used over the spectral range from 480 to 600 mis, and 3 cm. cells were used from 600 to 700 miA. The slit of the spectrometer was opened fairly wide during these observations so that more light could be gathered. This reduced the height of the oxy...

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confidence: 93%

The Relation of Methemoglobin to the Cyanosis Observed After Sulfanilamide Administration

Vigness¹,

Watson²,

Spink³

1940

J. Clin. Invest.

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“…Subsequent work by a number of investigators resulted in preparations of a cytosolic NADPH-dependent reductase that catalyzed the reduction of methylene blue and flavins and, in the presence of redox couplers, catalyzed the reduction of methemoglobin (4)(5)(6)(7)(8)(9). Whereas this NADPHdependent reductase is believed to contribute very little to methemoglobin reduction under normal conditions (10), its catalysis of methemoglobin reduction in the presence of methylene blue or riboflavin is the basis for the use of these compounds as therapeutic agents in the treatment of congenital and toxic methemoglobinemia (11)(12)(13). The erythrocyte reductase has variously been referred to as NADPH dehydrogenase, diaphorase, methemoglobin reductase, and, most recently, flavin reductase.…”

mentioning

confidence: 99%

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Xu¹,

Quandt²,

Hultquist³

1992

Proc. Natl. Acad. Sci. U.S.A.

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An NADPH-dependent reductase, first shown in the 1930s to catalyze the methylene blue-dependent reduction of methemoglobin in erythrocytes, has now been characterized as a high-affinity heme-binding protein and has been detected in liver. Highly purified bovine erythrocyte reductase binds protohemin to form a 1:1 complex with a Kd of 7 nM. Binding of protohemin completely inhibits reductase activity. Other tetrapyrroles and fatty acids also bind to the reductase and inhibit its activity. Protoporphyrin, hematoporphyrin, and coproporphyrin form 1:1 complexes withKd values ranging from 1 to 5 IzM. The inhibition constants for a number of saturated and unsaturated fatty acids range from 6 to 52 ,LM. A protein that is immunologically cross-reactive to the reductase has been detected in the cytosolic fractions of bovine and rat liver and of bovine, rat, rabbit, and human erythrocytes. By immunoblot analysis, the bovine liver and erythrocyte proteins appear identical in size, as do the rat liver and erythrocyte proteins. The concentration of the protein in bovine erythrocytes has been estimated by quantitative immunoblotting to be 10 juM. The detection of this protein in liver cells, the demonstration of its binding properties, and its weak reductase activity bring into question the long-held belief that this is uniquely an erythrocyte protein and that it functions as a reductase.Methylene blue stimulation of methemoglobin reduction in human erythrocytes was described 60 years ago by Warburg et al. (1), Steele and Spink (2), and Williams and Challis (3). Subsequent work by a number of investigators resulted in preparations of a cytosolic NADPH-dependent reductase that catalyzed the reduction of methylene blue and flavins and, in the presence of redox couplers, catalyzed the reduction of methemoglobin (4-9). Whereas this NADPHdependent reductase is believed to contribute very little to methemoglobin reduction under normal conditions (10), its catalysis of methemoglobin reduction in the presence of methylene blue or riboflavin is the basis for the use of these compounds as therapeutic agents in the treatment of congenital and toxic methemoglobinemia (11)(12)(13). The erythrocyte reductase has variously been referred to as NADPH dehydrogenase, diaphorase, methemoglobin reductase, and, most recently, flavin reductase.The reductase has been shown to bind small molecules. Isolation procedures generally yield two forms of the reductase, which exhibit very similar activities but different isoelectric points; one, but not the other, of these forms is reported to possess protein-bound NADP+ and a proteinbound yellow chromophore of unknown structure (7,8,(14)(15)(16). The isolation of the protein in the presence of flavin yields a flavoprotein (17). The protein isolated without the addition of flavin contains no flavin and yet exhibits full reductase activity.Recently (18) Bovine erythrocyte green heme-binding protein was purified as described (19). Antibodies to the green heme-binding protein were raised in young adult ...

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“…We realize that this neglects the observations that the cyanosis of sulfanilamide therapy may be due to methemoglobin (14,15).…”

Section: Methodsmentioning

confidence: 83%

Carbonic Anhydrase in Newborn Infants 1

Stevenson¹

1943

J. Clin. Invest.

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Carbonic anhydrase was described first in 1932 (1) as an enzyme which accelerates the reaction H2C03 = 12 + H20. Meldrum and Roughton (2) found that goat fetuses were low in carbonic anhydrase and stated, "In the very young fetuses, there is extraordinarily little enzyme and the amount does not begin to rise appreciably until very near the end of term." It was shown, further, that the enzyme is present with hemoglobin in the red blood cells (3) but is separable from these and gives the reactions of a zinc protein (4). The enzyme is inhibited by serum (5).It has been our impression for some time that premature and full-term newborn infants who are not thriving-e.g., showing poor color, feeble respirations, little or no gain in weight, low vitality are benefited by transfusions of whole blood from a compatible donor. With the above findings in mind, determinations of carbonic anhydrase were done on newborn infants in order to determine whether infants show a significant deficiency of carbonic anhydrase which can be restored by blood transfusions. METHODThe glass boat method, described by Meldrum and Roughton (2), was used. Two cc. of 0.2 M phosphate buffer (pH 6.8) were shaken vigorously with 2.0 cc. of 0.2 M sodium bicarbonate in an air tight chamber conr nected to a water manometer.

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A Study of Some of the Physiological Effects of Sulfanilamide. Ii. Methemoglobin Formation and Its Control

Cited by 54 publications

References 9 publications

The Relation of Methemoglobin to the Cyanosis Observed After Sulfanilamide Administration

The Relation of Methemoglobin to the Cyanosis Observed After Sulfanilamide Administration

Characterization of NADPH-dependent methemoglobin reductase as a heme-binding protein present in erythrocytes and liver.

Carbonic Anhydrase in Newborn Infants 1

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