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The Role of Nonhemoglobin Proteins and Reduced Glutathione in the Protection of Hemoglobin from Oxidation in Vitro

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The Role of Nonhemoglobin Proteins and Reduced Glutathione in the Protection of Hemoglobin from Oxidation in Vitro The Role of Nonhemoglobin Proteins and Reduced Glutathione in the Protection of Hemoglobin from Oxidation In Vitro A. S. Hill Jr., … , G. E. Cartwright, M. M. Wintrobe J Clin Invest. 1964;43(1):17-26. https://doi.org/10.1172/JCI104889. Research Article Find the latest version: https://jci.me/104889/pdf Journal of Clinical Investigatiox Vol. 43, No. 1, 1964 The Role of Nonhemoglobin Proteins and Reduced Glutathione in the Protection of Hemoglobin from Oxidation In Vitro * A. S. HILL, JR., A. HAUT, G. E. CARTWRIGHT, AND M. M. WINTROBE (From the Department of Medicine, University of Utah College of Medicine, Salt Lake City, Utah) A deficiency of reduced glutathione in erythro- human erythrocytes by Allen and Jandl (10) led cytes of freshly shed blood (1-4) or in erythro- these authors to conclude that GSH per se pro- cytes exposed to certain chemical compounds (5) tects hemoglobin from oxidation and that no ad- has been associated with shorter red cell survival ditional factors are required; conversely, Szein- and, in most cases, with the accumulation of oxi- berg and Marks (11) found that GSH affords no dation products of hemoglobin, including methe- protection to human hemoglobin against oxidative moglobin, sulfhemoglobin, and Heinz bodies. changes. The earlier report of Foulkes and Studies of "primaquine-sensitive" hemolytic dis- Lemberg (12) that GSH might oxidize hemo- ease have emphasized as a characteristic feature globin, along with the studies by Szeinberg and an "unstable" reduced glutathione (GSH) in the Marks (11) and Allen and Jandl (10), casts red cells, attributed to limited availability of re- doubt on the applicability to humans of the con- duced TPN (TPNH), the result, in turn, of a cept (13, 14), based on studies of rat blood (7, deficiency of the enzyme, glucose-6-phosphate 8), that an adequate amount of reduced glutathi- dehydrogenase - (G6PD). Despite extensive stud- one and the enzyme glutathione peroxidase to- ies of G6PD deficiency, it is still uncertain whether gether protect hemoglobin from oxidative break- the observations on reduced glutathione are of down. pathogenetic significance or are incidental. There Our experiments demonstrate, by the use of is even less information on the role of glutathione erythrocytes and hemoglobin from human sub- in certain cases of congenital methemoglobinemia jects, that in an in vitro system GSH can protect (1) and in hemolytic disease with (3, 4, 6) or hemoglobin from oxidizing agents and that this without (2) inclusion bodies, which have been protection is dependent upon a nonhemoglobin associated with abnormalities of glutathione. protein factor of erythrocytes, adduced to be Although these cases may suggest that reduced glutathione peroxidase. We further present an glutathione in the erythrocyte may be the final experimental basis for reconciliation of the pre- common pathway for various disorders affecting ceding contradictory reports concerning the role of oxidative hemolysis, the evidence conflicts as to glutathione. how, if at all, glutathione protects the healthy Methods erythrocyte from oxidative hemolysis. Mills (7-9) and Randall (7), after studies of Venous blood from hematologically normal and ap- parently healthy adults was anticoagulated with heparin. rat blood, concluded that GSH protects hemo- Plasma, buffy coat, and uppermost erythrocytes were globin from deleterious oxidative agents only in removed after prompt centrifugation at 5° C. The re- the presence of an additional factor, an enzyme maining red cells were washed three times each with they termed glutathione peroxidase. Studies of 4 vol of cold Krebs-Ringer phosphate buffer (7, 8), then stored at 50 C, and used as intact erythrocytes * Submitted for publication November 9, 1962; accepted within 48 hours. September 12, 1963. Preparation of whole hemolysate. Sufficient deionized This investigation was supported by a research grant water 1 was added to packed washed red cells to hemo- (AM-04489) and a graduate training grant (T1 AM- lyze them and reduce the hemoglobin concentration to 5098) from the National Institute of Arthritis and Meta- bolic Diseases, U. S. Public Health Service, Bethesda, 1 Deeminizer, Crystal Research Laboratories, Hart- Md. ford, Conn. 17 18 A. S. HILL, JR., A. HAUT, G. E. CARTWRIGHT, AND M. M. WINTROBE about 8 g per 100 ml. The hemolysate was kept at about Samples for the determination of hemoglobin pig- 50 C and was used without further centrifugation within ment were placed in 25- X 40-mm glass tubes and sub- 48 hours of the time of its preparation. jected to 20 kc ultrasound at 4 amp power input at cavi- Preparation of hemoglobin solution. Sufficient de- tary resonance for 5 seconds.3 This insured complete ionized water was added to washed erythrocytes to hemolysis and did not affect the proportion of hemoglo- hemolyze them and to yield about 8 ml of solution with bin derivatives. The samples, after centrifugation at a hemoglobin concentration of about 10 g per 100 ml. 2,000 X g for 5 minutes, were clear. To this was added 15 g of diethylaminoethyl (DEAE) Methemoglobin, sulfhemoglobin, oxyhemoglobin, and cellulose from which excess water had been removed. total hemoglobin were determined by the method of DEAE had been prepared according to the method of Evelyn and Malloy (21). Results are expressed as Hennessey, Haffner, and Gabrio (15; also Waltersdorph per cent of the total hemoglobin at time zero. "Precipi- and Huennekens, 16), except for the addition of a final tated hemoglobin" was calculated by subtracting the series of washes with deionized water, continued until the measured total hemoglobin from the hemoglobin at time supernatant fluid gave a negative phosphate test with silver zero. In one experiment the precipitated hemoglobin was nitrate. After the mixture of DEAE cellulose and collected and weighed. hemolysate was stirred for about 5 minutes, the hemo- Catalase was determined by the method used by Taka- globin solution was separated f rom the cellulose by hara and co-workers (22), except that the determinations suction, through the use of a coarse, sintered glass funnel. were carried out at 200 C. Glucose-6-phosphate dehy- The filtrate, containing about 8 g of hemoglobin per drogenase was determined in the manner of Kornberg and 100 ml, was the hemoglobin solution employed in these Horecker (23) as modified by Marks, Szeinberg, and experiments; it was kept cold and used within 48 hours Banks (24). Pyruvate kinase was determined by the of the time of preparation. The hemoglobin solution method of Bucher and Pfleiderer (25) as modified by was found to be devoid of catalase, G6PD, pyruvate Valentine, Tanaka, and Miwa (26). Glutathione perox- kinase, and glutathione peroxidase activities and to con- idase was determined by a modification of method num- tain carbonic anhydrase activity, each assayed by tech- ber two of Mills (9). Carbonic anhydrase was deter- niques described below. The whole hemolysate contained mined by the technique of Wilbur and Anderson (27). all of these enzymatic activities. The nonhemoglobin Glutathione reductase was determined by the mode of protein solution, described below, contained all of these Schrier and co-workers (28). activities except carbonic anhydrase. The data were treated as nonindependent variables. Preparation of nonhemoglobin protein solution. After A p value of less than 0.05 was considered to be sig- extraction of the hemoglobin solution by suction, the nificant (29). cellulose was washed three times in a total of 4,500 ml of cold, deionized water. Excess water was expressed, Results and the cellulose was treated with 4 ml of 0.4 M phos- phate buffer, pH 7.1. The eluate was separated on a Effect of ascorbic acid on the formation of sulf- coarse, sintered glass funnel and then was used to re- hemoglobin in washed erythrocytes, whole hemoly- extract the cellulose. The resulting yellow solution was sates, and hemoglobin solutions. The formation termed the nonhemoglobin protein (NHP) solution. The ratio of the absorbance at 280 mAt to that at the of oxidative derivatives of hemoglobin in intact Soret band (420 m/is) was 2:1 for the NHP solution, erythrocytes, whole hemolysates, and hemoglobin whereas that of the hemoglobin solution was 1: 4. solutions was zero in 2 hours. Ascorbic acid or Preparation of reagents. Preliminary experiments in- acetylphenylhydrazine was therefore added to the dicated that satisfactory stability of GSH2 could be incubation flasks to accelerate these oxidative obtained in 0.15 M sodium chloride or in 0.4 M phosphate buffer (pH 7.1) if the solutions were prepared within changes, against which the effects of various com- 4 hours of the experiments, if siliconized glassware was pounds could be measured. used, and if the solutions contained EDTA. All ascorbic The augmentation of sulfhemoglobin formation acid and acetylphenylhydrazine solutions were adjusted produced by the addition of ascorbic acid was to pH 7.1 with 0.15 M sodium carbonate and were made greatest when the substrate was hemoglobin solu- within 1 hour of their use. Chemical determinations and enzyme assays. Reduced tion, least when the substrate was intact erythro- glutathione was determined by the method used by Mills cytes, and intermediate in the case of whole he- (9) based on principles outlined by Boyer (17) and molysate (Table I). also by the technique of Grunert and Phillips (18) as Effect of GSH on the formation of sulfhemo- modified by Beutler (19). Oxidized glutathione was de- globin in whole hemolysates and hemoglobin
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