• Volume 69 , Number 3
  • Page: 247–9

Dapsone-lnduced Methemoglobinemia in leprosy patients

Inderjeet Kaur; Manjula Mehta; Natini Agnihotri; Sunil Dogra; N. K. Ganguly

This department is for the publication of informal communications that are of interest because they are informative and stimulating, and for the discussion of controversial matters. The mandate of this Journal is to disseminate in formation relating to leprosy in particular and also other mycobacterial diseases. Dissident comment or interpretation on published research is of course valid, but personality attacks on individuals would seem unnecessary. Political comments, valid or not, also are unwelcome. They might result in interference with the distribution of the Journal and thus interfere with its prime purpose.

To the Editor:

Diaminodiphenylsulfone (dapsone) is one of the most widely used drugs being given to millions of leprosy patients for the last six decades. Considering the enormous number of persons receiving dapsone, severe toxic reactions are rare (4). Methemoglobinemia as a toxic effect with dapsone in high doses has been well documented (3). However, clinically significant methemoglobinemia as a hematological side effect of dapsone is rare at therapeutic doses (4).

Methemoglobin is an oxidized product of hemoglobin in which heme iron becomes Fe3+ and is incapable of binding oxygen. Normally, a low level of methemoglobin is maintained in the blood due to activity of the cytochrome b5 reductase (methemoglobin reductase) enzyme (5). Malaria prophylaxis has been reported as provoking methemoglobinemia in unsuspected hetero- zygotic individuals deficient in NADH- cytochrome b. reductase enzyme (1). The present study was designed to investigate the role of cytochrome b5 reductase activity in dapsone-induced methemoglobin production in leprosy patients.

Twenty, untreated, newly diagnosed patients with leprosy (8 BL/LL. 12 BT/TT) and 10 healthy age- and sex-matched controls attending Nehru Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh, India, were enrolled in the study. Blood samples were collected from all leprosy subjects prior to and after treatment with the 1982 World Health Organization (WHO) multidrug therapy fWHO/MDT). All samples were tested for oxyhemoglobin and methemoglobin levels using standard (biochemical) methods. NADH-methemoglobin reductase enzyme activity was estimated by a slightly modified technique of Scott, et al. O, using erythrocytes of blood conserved in ACD, removing excess nitrite, 10 ml of double distilled water was added to 0.05 ml of packed cells. Finally, absorbance was determined at 600 nm against distilled water. Then to 3 ml of hemolysate, 0.2 of 0.012 M 2, 6-dichlorobenzenone indephenol (DCIP) in I M Tris-HCl buffer (pH = 7.6) containing 0.011 M disodium EDTA was added. The enzyme activity was studied using 0.008 M NADH. and the enzyme activity expressed in change in absorbance per minute at 600 nm (A x 600/min x 104). All patients were also screened for glucose 6-phosphate dehydrogenase (G-6-PD) deficiency.

There were 12 male and 8 female leprosy patients with ages ranging from 12 to 47 years. Mean hemoglobin levels were found to be significantly decreased (p <0.05) in leprosy patients after therapy (WHO/MDT) compared to before therapy. After treatment, a slight but significant increase (p <0.01) in methemoglobin levels was observed in leprosy patients as compared to control subjects. There was a statistically significant decrease in the activity of the methemoglobin reductase enzyme after treatment in patients compared to controls (p <0.01). Similar observations have also been made in another two studies of leprosy patients in the past (6-8). None of our patients had significantly raised methemoglobin levels to manifest clinically. A" patients screened for G-6-PD deficiency were found to be normal. Manfredi, et al. (7) also concluded that hemolytic anemia and methemoglobinemia in patients taking dapsone is not due to functional impairment of the G-6-PD enzyme.

Acquired methemoglobinemia results from exposure to certain drugs and chemicals, such as nitrite, chlorate, and sulfonamide compounds capable of oxidizing hemoglobin directly or indirectly. The exact mechanism by which dapsone induces methemoglobinemia in vivo is not known, but the drug metabolite 4-amino-4-hydroxy- aminodiphenylsulfone is said to be responsible for oxidation (9).

The NADH-dependent reductase system associated with cytochrome b. represents one of the major electron transport systems in the body which covert methemoglobin to hemoglobin (The Figure). So, we propose that a decrease in activity of the NADH- methemoglobin reductase enzyme, as observed in our study, might be one of the major factors responsible for dapsone-induced methemoglobinemia in leprosy patients. The growing numbers of immunosup- pressed patients due to the spread of HIV infection may result in increased dapsone use for Pneumocystis carinii pneumonia (PCP) prophylaxis (10). Although methemoglobinemia occurring at therapeutic doses of dapsone is generally asymptomatic, clinicians should be aware of this adverse effect, and patients presenting with respiratory distress of unknown etiology should be evaluated for methemoglobinemia.


The Figure. The interconversion Of hemoglobin and methemoglobin.


- Inderjeet Kaur, M.D., M.N.A.M.S.

Additional Professor
Department of Dermatology, Venereology and Leprology

- Manjula Mehta, Ph.D.
Natini Agnihotri, Ph.D.

Department of Experimental Medicine

- Sunil Dogra, M.D., D.N.B.

Department of Dermatology, and Leprology

- N. K. Ganguly, M.D.

Department of Experimental Medicine
Postgraduate Institute of Medical Education and Research
Chandigarh 160 012, India



1. Cohen, R. J., Sachs, J. R., Wicher, D. J. and Conrad, M. E. Methemoglobinemia provoked by malarial prophylaxis in Vietnam. N. Engl. J. Med. 279(1968)1127-1131.

2. Coken, J. N. Methemoglobinemia and other disorders accompanied by cyanosis. In: Wintrobe's Clinical Hematology. 9th edn. Lee, G. R., Bithell, T. C., Foerster, J., Athens, J. W. and Lukens, J. N., eds. Philadelphia: Lea and Febiger, 1993, pp. 1262-1271.

3. Frey, H. M., Gershon, A. A. and Borkowsky, W. Fatal reaction to dapsone during treatment of leprosy. Ann. Int. Med. 94(1981)777-778.

4. Katz, I. S. Dapsone. In: Dermatology in General Medicine. 4th edn. Fitzpatrick, T. B., Eisen, A. Z., Wolff, K., Freedberg, I. M. and Austen, K. F., eds. New York: McGraw-Hill, Inc., 1993, pp. 2865-2868.

5. Kranier, R A., Glader, B. E. and Li, T. K. Mechanism of methemoglobin formation by diphenylsulfones. Effect of 4-amino, 4-hydroxyaminodiphenyl-sufone and other p-substituted derivatives. Biochem. Pharmacol. 21(1972)1265-1274.

6. Magna, L. A. and Beiguelman, B. NADH- methemoglobin reductase and methemoglobinemia among leprosy patients. Int. J. Lepr. 52(1984)457-481.

7. Manfredi, G., De panfilis, G., Zampetti, M. and Allegra, F. Studies on dapsone induced hemolytic anaemia. Methaemoglobin production and G-6-PD activity in correlation with dapsone dosage. Br. J. Dermatol. 100(1979)427-432.

8. Queiroz, R. H., Melchior, J. E., de Souza, A. M., Gouveia, E., Barbara, J. C. and de Carvalho, D. Haematological and biochemical alterations in leprosy patients already treated with dapsone and MDT. Pharm. Acta Helv. 72(1997)209-213.

9. Scott, K. M. The relation of diaphorase of human erythrocytes to inheritance of methemoglobinemia. J. Clin. Invest. 39(1960)1176-1177.

10. Ward, K. E. and McCarthy, M. W. Dapsone- induced methemoglobinemia. Ann. Pharmacother. 32(1998)549-553.











Reprint requests to Dr. Kaur at the above address or FAX 91-0172-744-401; e-mail: kaur_inderjeet@yahoo.com

2024 © International Journal of Leprosy and other Mycobacterial Diseases all right reaserved GN1