J Clin Invest 46(12): 1986-1998

PMC: PMC292951

PMID: 6074003

doi: 10.1172/JCI105688

Carbon Monoxide Production Associated with Ineffective Erythropoiesis<sup><a href="#fn1" rid="fn1" class=" fn">*</a></sup>

Abstract

After administration of glycine-2-^{C to these patients, endogenous CO was isolated by washout of body CO stores at high pO}₂ or by reacting peripheral venous blood samples with ferricyanide. The CO was then oxidized to CO₂ by palladium chloride and trapped for counting in a liquid scintillation spectrometer. “Early labeled” peaks of ^{CO were demonstrated which paralleled “early labeled” peaks of stercobilin and preceded maximal labeling of circulating heme. Production of “early labeled”}^{CO in patients with ineffective erythropoiesis was greatly increased, up to 14 times that found in a normal subject.}

The increased ˙Vco and “early ^{CO” production shown by these patients are presumably related mainly to heme catabolism in the marrow. The possibility exists that hepatic heme and porphyrin compounds may also contribute significantly to}˙Vco, as suggested by the finding of a high ˙Vco in an additional patient with porphyria cutanea tarda.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.8M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

LONDON IM, WEST R, SHEMIN D, RITTENBERG D. On the origin of bile pigment in normal man. J Biol Chem. 1950 May;184(1):351–358. [PubMed] [Google Scholar]
GRAY CH, NEUBERGER A, SNEATH PHA. Studies in congenital porphyria. 2. Incorporation of 15N in the stercobilin in the normal and in the porphyric. Biochem J. 1950 Jun-Jul;47(1):87–92.[PMC free article] [PubMed] [Google Scholar]
GRAY CH, SCOTT JJ. The effect of haemorrhage on the incorporation of [alpha-14C]Glycine into stercobilin. Biochem J. 1959 Jan;71(1):38–42.[PMC free article] [PubMed] [Google Scholar]
Barrett PV, Cline MJ, Berlin NI. The association of the urobilin "early peak" and erythropoiesis in man. J Clin Invest. 1966 Nov;45(11):1657–1667.[PMC free article] [PubMed] [Google Scholar]
YAMAMOTO T, SKANDERBEG J, ZIPURSKY A, ISRAELS LG. THE EARLY APPEARING BILIRUBIN: EVIDENCE FOR TWO COMPONENTS. J Clin Invest. 1965 Jan;44:31–41.[PMC free article] [PubMed] [Google Scholar]
Robinson SH, Owen CA, Jr, Flock EV, Schmid R. Bilirubin formation in the liver from nonhemoglobin sources. Experiments with isolated, perfused rat liver. Blood. 1965 Dec;26(6):823–829. [PubMed] [Google Scholar]
Robinson SH, Tsong M, Brown BW, Schmid R. The sources of bile pigment in the rat: studies of the "early labeled" fraction. J Clin Invest. 1966 Oct;45(10):1569–1586.[PMC free article] [PubMed] [Google Scholar]
LONDON IM, WEST R. The formation of bile pigment in pernicious anemia. J Biol Chem. 1950 May;184(1):359–364. [PubMed] [Google Scholar]
LONDON IM, WEST R, SHEMIN D, RITTENBERG D. Porphyrin formation and hemoglobin metabolism in congenital porphyria. J Biol Chem. 1950 May;184(1):365–371. [PubMed] [Google Scholar]
GRINSTEIN M, BANNERMAN RM, VAVRA JD, MOORE CV. Hemoglobin metabolism in thalassemia. In vivo studies. Am J Med. 1960 Jul;29:18–32. [PubMed] [Google Scholar]
JAMES GW, 3rd, ABBOTT LD., Jr Stercobilin N15 excretion in refractory anemia. Trans Am Clin Climatol Assoc. 1961;73:110–120.[PMC free article] [PubMed] [Google Scholar]
GIBLETT ER, COLEMAN DH, PIRZIOBIROLI G, DONOHUE DM, MOTULSKY AG, FINCH CA. Erythrokinetics: quantitative measurements of red cell production and destruction in normal subjects and patients with anemia. Blood. 1956 Apr;11(4):291–309. [PubMed] [Google Scholar]
HAURANI FI, TOCANTINS LM. Ineffective erythropoiesis. Am J Med. 1961 Oct;31:519–531. [PubMed] [Google Scholar]
WATSON CJ. Recent studies of the urobilin problem. J Clin Pathol. 1963 Jan;16:1–11.[PMC free article] [PubMed] [Google Scholar]
OSTROW JD, JANDL JH, SCHMID R. The formation of bilirubin from hemoglobin in vivo. J Clin Invest. 1962 Aug;41:1628–1637.[PMC free article] [PubMed] [Google Scholar]
COBURN RF, BLAKEMORE WS, FORSTER RE. Endogenous carbon monoxide production in man. J Clin Invest. 1963 Jul;42:1172–1178.[PMC free article] [PubMed] [Google Scholar]
Coburn RF, Williams WJ, White P, Kahn SB. The production of carbon monoxide from hemoglobin in vivo. J Clin Invest. 1967 Mar;46(3):346–356.[PMC free article] [PubMed] [Google Scholar]
COBURN RF, WILLIAMS WJ, FORSTER RE. EFFECT OF ERYTHROCYTE DESTRUCTION ON CARBON MONOXIDE PRODUCTION IN MAN. J Clin Invest. 1964 Jun;43:1098–1103.[PMC free article] [PubMed] [Google Scholar]
Coburn RF, Williams WJ, Kahn SB. Endogenous carbon monoxide production in patients with hemolytic anemia. J Clin Invest. 1966 Apr;45(4):460–468.[PMC free article] [PubMed] [Google Scholar]
HERBERT V. The assay and nature of folic acid activity in human serum. J Clin Invest. 1961 Jan;40:81–91.[PMC free article] [PubMed] [Google Scholar]
RAMSAY WN. The determination of iron in blood plasma or serum. Clin Chim Acta. 1957 Jun;2(3):214–220. [PubMed] [Google Scholar]
LOEFFLER RK, RAPPOPORT DA, COLLINS VP. Radioiron citrate as tracer to determine disappearance rate of plasma iron in normal subjects. Proc Soc Exp Biol Med. 1955 Mar;88(3):441–444. [PubMed] [Google Scholar]
READ RC. Studies of red-cell volume and turnover using radiochromium; description of a new closed method of red-cell volume measurement. N Engl J Med. 1954 Jun 17;250(24):1021–1027. [PubMed] [Google Scholar]
COBURN RF, DANIELSON GK, BLAKEMORE WS, FORSTER RE., 2nd CARBON MONOXIDE IN BLOOD: ANALYTICAL METHOD AND SOURCES OF ERROR. J Appl Physiol. 1964 May;19:510–515. [PubMed] [Google Scholar]
OSTROW JD, HAMMAKER L, SCHMID R. The preparation of crystalline bilirubin-C14. J Clin Invest. 1961 Aug;40:1442–1452.[PMC free article] [PubMed] [Google Scholar]
NATHAN DG, GABUZDA TG, GARDNER FH. LIQUID SCINTILLATION COUNTING OF C14-LABELED HEMOGLOBIN AND HEMIN BY A MODIFIED SCHOENIGER TECHNIQUE. J Lab Clin Med. 1963 Sep;62:511–516. [PubMed] [Google Scholar]
ALLEN TH, ROOT WS. Colorimetric determination of carbon monoxide in air by an improved palladium chloride method. J Biol Chem. 1955 Sep;216(1):309–317. [PubMed] [Google Scholar]
CLINE MJ, BERLIN NI. The red cell chromium elution rate in patients with some hematologic diseases. Blood. 1963 Jan;21:63–69. [PubMed] [Google Scholar]
DORNHORST AC. The interpretation of red cell survival curves. Blood. 1951 Dec;6(12):1284–1292. [PubMed] [Google Scholar]
Coburn RF, Forster RE, Kane PB. Considerations of the physiological variables that determine the blood carboxyhemoglobin concentration in man. J Clin Invest. 1965 Nov;44(11):1899–1910.[PMC free article] [PubMed] [Google Scholar]
WITTENBERG J, SHEMIN D. The location in protoporphyrin of the carbon atoms derived from the alpha-carbon atom of glycine. J Biol Chem. 1950 Jul;185(1):103–116. [PubMed] [Google Scholar]
JAMES GW, 3rd, ABBOTT LD., Jr Erythrocyte destruction in sickle-cell anemia: simultaneous N15-hemin and N15-stercobilin studies. Proc Soc Exp Biol Med. 1955 Mar;88(3):398–402. [PubMed] [Google Scholar]
NOMOF N, HOPPER J, Jr, BROWN E, SCOTT K, WENNESLAND R. Simultaneous determinations of the total volume of red blood cells by use of carbon monoxide and chromium in healthy and diseased human subjects. J Clin Invest. 1954 Oct;33(10):1382–1387.[PMC free article] [PubMed] [Google Scholar]
Landaw SA, Winchell HS. Endogenous production of carbon-14 labeled carbon monoxide: an in vivo technique for the study of heme catabolism. J Nucl Med. 1966 Sep;7(9):696–707. [PubMed] [Google Scholar]
LONDON IM. The conversion of hematin to bile pigment. J Biol Chem. 1950 May;184(1):373–376. [PubMed] [Google Scholar]
Pass IJ, Schwartz S, Watson CJ. THE CONVERSION OF HEMATIN TO BILIRUBIN FOLLOWING INTRAVENOUS ADMINISTRATION IN HUMAN SUBJECTS. J Clin Invest. 1945 May;24(3):283–291.[PMC free article] [PubMed] [Google Scholar]
SNYDER AL, SCHMID R. THE CONVERSION OF HEMATIN TO BILE PIGMENT IN THE RAT. J Lab Clin Med. 1965 May;65:817–824. [PubMed] [Google Scholar]
Schmid R, Marver HS, Hammaker L. Enhanced formation of rapidly labelled bilirubin by phenobarbital: hepatic microsomal cytochromes as a possible source. Biochem Biophys Res Commun. 1966 Aug 12;24(3):319–328. [PubMed] [Google Scholar]
REMMER H, MERKER HJ. EFFECT OF DRUGS ON THE FORMATION OF SMOOTH ENDOPLASMIC RETICULUM AND DRUG-METABOLIZING ENZYMES. Ann N Y Acad Sci. 1965 Mar 12;123:79–97. [PubMed] [Google Scholar]
LOWRY PT, HAWKINSON V, WATSON CJ. An isotopic study of type III porphyrins and hemoglobin metabolism in an unusual case of "mixed" porphyria. Metabolism. 1952 Mar;1(2):149–154. [PubMed] [Google Scholar]

^{Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania}

^{Department of Physiology, Graduate Division, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania}

^{Trainee in Hematology under Training Grant T1-AM-5228 from the National Institute of Arthritis and Metabolic Disease, National Institutes of Health, Bethesda, Md.}

^{Recipient of U. S. Public Health Service Research Career Program Award K3-HE-11, 564 from the National Heart Institute.}

^{Recipient of U. S. Public Health Service Research Career Program Award K3-HE-2629 from the National Heart Institute.}

Address requests for reprints to Dr. Peter White, Hospital of the University of Pennsylvania, Philadelphia, Pa. 19104.

^{Received for publication 8 March 1967 and in revised form 19 July 1967.}

Presented in part before the American Society of Hematology, Seattle, Wash., November 1964 (Blood. 1964. 24: 845. Abstr.). Supported in part by Grant AM-07301, from the National Institute of Arthritis and Metabolic Diseases, U. S. Public Health Service, Bethesda, Md., the Life Insurance Medical Research Fund, and Clinical Research Center Grant 3MO1 FR-40, Division of Research Facilities and Resources, National Institutes of Health.

Address requests for reprints to Dr. Peter White, Hospital of the University of Pennsylvania, Philadelphia, Pa. 19104.

Abstract

The rate of endogenous carbon monoxide production (˙Vco), determined by the closed rebreathing system technique, was elevated above the normal range in four of five patients studied with ineffective erythropoiesis (four patients with primary refractory anemia, one with thalassemia). The mean molar ratio of ˙Vco to ˙Vheme (rate of circulating heme catabolism, determined from ^{Cr red cell survival curves) was 3.0 ± 0.6 (SE), indicating that most of the CO originated from sources other than circulating erythrocyte hemoglobin, in contrast to previous findings in patients with hemolytic anemia, where}˙Vco paralleled ˙Vheme closely.After administration of glycine-2-^{C to these patients, endogenous CO was isolated by washout of body CO stores at high pO}₂ or by reacting peripheral venous blood samples with ferricyanide. The CO was then oxidized to CO₂ by palladium chloride and trapped for counting in a liquid scintillation spectrometer. “Early labeled” peaks of ^{CO were demonstrated which paralleled “early labeled” peaks of stercobilin and preceded maximal labeling of circulating heme. Production of “early labeled”}^{CO in patients with ineffective erythropoiesis was greatly increased, up to 14 times that found in a normal subject.}The increased ˙Vco and “early ^{CO” production shown by these patients are presumably related mainly to heme catabolism in the marrow. The possibility exists that hepatic heme and porphyrin compounds may also contribute significantly to}˙Vco, as suggested by the finding of a high ˙Vco in an additional patient with porphyria cutanea tarda.