Isoniazid acetylating phenotype in patients with paracoccidioidomycosis and its relationship with serum sulfadoxin levels, glucose-6-phosphate dehydrogenase and glutathione reductase activities

Barraviera, Benedito; Pereira, Paulo Câmara Marques; Machado, Jussara Marcondes; Souza, Maria Julia de; Lima, Carlos Roberto G.; Curi, Paulo Roberto; Mendes, Rinaldo Poncio; Meira, Domingos Alves

doi:10.1590/S0037-86821991000200008

Abstracts

The authors evaluated the isoniazid acetylating phenotype and measured hematocrit, hemoglobin, glucose-6-phosphate dehydrogenase and glutathione reductase activities plus serum sulfadoxin levels in 39 patients with paracoccidioidomycosis (33 males and 6 females) aged 17 to 58 years. Twenty one (53.84%) of the patients presented a slow acetylatingphenotype and 18(46.16%) a fast acetylating phenotype. Glucose-6-phosphate- dehydrogenase (G6PD) acti vity was decreased in 5(23.80%) slow acetylators and in 4(22.22%) fast acetylators. Glutathione reductase activity was decreased in 14 (66.66%) slow acetylators and in 12 (66.66%) fast acetylators. Serum levels of free and total sulfadoxin Were higher in slow acetylator (p < 0.02). Analysis of the resultspermitted us to conclude that serum sulfadoxin levels are related to the acetylatorphenotype. Furthermore, sulfadoxin levels were always above 50 µg/ml, a value considered therapeutic. Glutathione reductase deficiency observed in 66% of patients may be related to the intestinal malabsorption of nutrients, among them riboflavin, a FAD precursor vitamin, inpatients with paracoceidioidomycosis.

Isoniazid acetylating phenotype; Paracoccidioidomycosis; Glucose-6-phosphate dehydrogenase (G6PD); Glutathione reductase; Sulfadoxin

Os autores avaliaram o fenótipo acetilador da isoniazida, hematócrito, hemoglobina, atividade da glicose-6- fosfato desidrogenase, glutationa redutase e os níveis séricos de sulfadoxina de 39 doentes com paracoccidíoidomicose, senão 33 do sexo masculino e 6 do feminino, com idades compreendidas entre 17 e 58 anos. Vinte e um (53,84%) doentes apresentaram fenótipo acetilador lento e 18 (46,16%) rápido. A atividade da glicose-6-fosfato desidrogenase (G6PD) esteve diminuída em 5 (23,80%) acetiladores lentos e 4 (22,22%) rápidos. A atividade da glutationa redutase esteve diminuída em 14 (66,66%) acetiladores lentos e 12 (66,66%) rápidos. Os níveis séricos de sulfadoxina livre e total foram maiores nos acetiladores lentos (p < 0,02). A análise dos resultados permite concluir que os níveis séricos de sulfadoxina relaciona-se com o fenótipo acetilador. Além disso, os níveis estiveram sempre acima de 50 µg/ml, níveis estes considerados terapêuticos. Por outro lado, a deficiência de glutationa redutase pode estar relacionada com a má absorção intestinal de nutrientes, entre eles riboflavina, vitamina precursora de FAD.

Fenótipo acetilador da isoniazida; Paracoccidioidomicose; Glicose-6-fosfato desidrogenase (G6PD); Glutationa redutase; Sulfadoxina

ARTICLES

Isoniazid acetylating phenotype in patients with paracoccidioidomycosis and its relationship with serum sulfadoxin levels, glucose-6-phosphate dehydrogenase and glutathione reductase activities

Benedito Barraviera; Paulo Câmara Marques Pereira; Jussara Marcondes Machado; Maria Julia de Souza; Carlos Roberto G. Lima; Paulo Roberto Curi; Rinaldo Poncio Mendes; Domingos Alves Meira

^{Adress to correspondence} Adress to correspondence: Dr. Benedito Barraviera Faculdade de Medicina de Botucatu/UNESP CP: 576 18610 Botucatu, SP, Brasil.

ABSTRACT

The authors evaluated the isoniazid acetylating phenotype and measured hematocrit, hemoglobin, glucose-6-phosphate dehydrogenase and glutathione reductase activities plus serum sulfadoxin levels in 39 patients with paracoccidioidomycosis (33 males and 6 females) aged 17 to 58 years. Twenty one (53.84%) of the patients presented a slow acetylatingphenotype and 18(46.16%) a fast acetylating phenotype. Glucose-6-phosphate- dehydrogenase (G6PD) acti vity was decreased in 5(23.80%) slow acetylators and in 4(22.22%) fast acetylators. Glutathione reductase activity was decreased in 14 (66.66%) slow acetylators and in 12 (66.66%) fast acetylators. Serum levels of free and total sulfadoxin Were higher in slow acetylator (p < 0.02). Analysis of the resultspermitted us to conclude that serum sulfadoxin levels are related to the acetylatorphenotype. Furthermore, sulfadoxin levels were always above 50 µg/ml, a value considered therapeutic. Glutathione reductase deficiency observed in 66% of patients may be related to the intestinal malabsorption of nutrients, among them riboflavin, a FAD precursor vitamin, inpatients with paracoceidioidomycosis.

Keywords: Isoniazid acetylating phenotype. Paracoccidioidomycosis. Glucose-6-phosphate dehydrogenase (G6PD). Glutathione reductase. Sulfadoxin.

RESUMO

Os autores avaliaram o fenótipo acetilador da isoniazida, hematócrito, hemoglobina, atividade da glicose-6- fosfato desidrogenase, glutationa redutase e os níveis séricos de sulfadoxina de 39 doentes com paracoccidíoidomicose, senão 33 do sexo masculino e 6 do feminino, com idades compreendidas entre 17 e 58 anos. Vinte e um (53,84%) doentes apresentaram fenótipo acetilador lento e 18 (46,16%) rápido. A atividade da glicose-6-fosfato desidrogenase (G6PD) esteve diminuída em 5 (23,80%) acetiladores lentos e 4 (22,22%) rápidos. A atividade da glutationa redutase esteve diminuída em 14 (66,66%) acetiladores lentos e 12 (66,66%) rápidos. Os níveis séricos de sulfadoxina livre e total foram maiores nos acetiladores lentos (p < 0,02). A análise dos resultados permite concluir que os níveis séricos de sulfadoxina relaciona-se com o fenótipo acetilador. Além disso, os níveis estiveram sempre acima de 50 µg/ml, níveis estes considerados terapêuticos. Por outro lado, a deficiência de glutationa redutase pode estar relacionada com a má absorção intestinal de nutrientes, entre eles riboflavina, vitamina precursora de FAD.

Palavras-chave: Fenótipo acetilador da isoniazida. Paracoccidioidomicose. Glicose-6-fosfato desidrogenase (G6PD). Glutationa redutase. Sulfadoxina.

Full text available only in PDF format.

Texto completo disponível apenas em PDF.

Recebido para publicação em 28/12/90.

Department of Infectious and Parasitologic Diseases, and Section of Statistics, School of Medicine of Botucatu, University Paulist State, São Paulo, SP, Brazil.

Research Supported by FUNDUNESP, Grant 007/89 and CNPq, Grant 300398/88-3.

1. Barraviera B. Effect of antimalarial drugs and of clindamycin on erythrocyte metabolism. A review. Revista do Instituto de Medicina Tropical de São Paulo 31:200- 205, 1989.
2. Barraviera B, Machado PEA, Meira DA. Glutathion reductase activity and its relation with riboflavin levels measured by methemoglobin reduction by cystamine in patients with malaria. (Preliminary Report). Revista do Instituto de Medicina Tropical de São 30: 107-108, 1988.
3. Barraviera B, Machado PEA, Meira DA, Curi PR, Martins JNP, Souza MJ. Glucose-6-phosphate dehydrogenase and glutathione reductase activity in methemoglobin reduction by methylene blue and cystamine. Study on gIucose-6-phosphate dehydrogenase-deficient individuals, on normal subjects and on riboflavin-treated subjects. Revista do Instituto de Medicina Tropical de São Paulo 30: 370-378,1988.
4. Barraviera B, Meira DA, Machado PEA, Curi PR. Malária no município de Humaitá, Estado do Amazonas XXI. Prevalência da deficiência de glicose-6-fosfato desidrogenase (G6PD) em amostra da população e em doentes com malária causada pelo Plasmodium falciparum . Revista do Institute de Medicina Tropical de São Paulo 29: 374-380,1987.
5. Barraviera B, Mendes RP, Machado JM, Pereira PCM, Souza MJ, Meira DA. Evaluation of treatment of paracoccidioidomycosis with cotrimazine (combination of sulfadiazine and trimethoprim). Revista do Institute de Medicina Tropical de São Paulo 31: 53-55, 1989.
6. Barraviera B, Mendes RP, Pereira PCM, Machado JM, Curi PR, Meira DA. Measurement of glucose-6-phosphate dehydrogenase and glutathione reductase activity in patients with paracoccidioidomycosis treated with ketoconazole. Mycopathologia 104: 87-91, 1988.
7. Barraviera B, Paiva SAR, Marques MEA, Machado JCMS. Paracoccidioidomicose subaguda progressiva. Tratamento de um doente com cotrimoxazole e nutrição parenteral. Arquivos Brasileiros de Medicina 63: 406- 410, 1989.
8. Barraviera B, Pereira PCM, Mendes RP, Machado JM, Lima CRG, Meira DA. Evaluation of acetylator phenotype, renal function and serum sulfadiazine levels in patients with paracoccidioidomycosis treated with cotrimazine (combination, of sulfadiazine and trimethoprim). Mycopathologia 108: 107-112, 1989.
9. Barraviera SRCS, Barraviera B, Machado PEA, Habermann MC, Stolf HO, Gonzaga HFS. Uso da riboflavina no tratamento da hemólise pela sulfona em doente com dermatite herpetiforme de Duhring-Brocq deficiente em glutationa redutase. Anais Brasileiros de Dermatologia 64: 231-233, 1989.
10. BeiguelmanB, Ramalho AS, ArenaJFP, GarlippCR. A acetilação da isoniazida em brasileiros caucasóides e negróides com tuberculose pulmonar. Revista Paulista de Medicina 89: 12-15, 1977.
11. Bratton AC, Marshall EK. A new coupling component for sulfanilamide. Journal of Biological Chemistry 128: 537-550, 1939.
12. Eidus L, Varughese P, Hodgkin MM, Hsu AHE, McRae KB. Simplification of isoniazid phenotyping procedure to promote its aplication in the chemoterapy of tuberculosis. Bulletin of the World Health Organization 49:507- 516, 1973.
13. Franco MF, Montenegro MR, Mendes RP, Marques SA, Dillon NL, Mota NGS. Paracoccidioidomycosis: a recently proposed classification of its clinical forms. Revista da Sociedade Brasileira de Medicina Tropical 20: 129-132, 1987.
14. Grimes AJ. Human red cell metabolism. Blackwell, London, 1980.
15. Hodgkin MM, Eidus L, Hamilton EJ. Screening of isoniazid inactivators by dilution test Bulletin of the World Health Organization 51: 428-430, 1974.
16. Marcondes JM, Meira DA, Machado PEA, Barraviera B, Matsubara LS, Vadileti C, Pirolla JAG, Machado EAB. Malária no município de Humaitá, Estado do 'Amazonas XIV - Inquérito coprológico em habitantes da região em relação às taxas de hemoglobina. Revista do Instituto de Medicina Tropical de São Paulo 24(supl 6): 24-28, 1982.
17. Martinez R, Meneghelli VG, Fiorillo AM, Oliveira RB. O comprometimento gastrintestinal na blastomicose sul- americana (Paracoccidioidomicose) II. Estudo funcional do intestino delgado. Revista da Associação Médica Brasileira 25: 70-72, 1979.
18. Mendes RP. Paracoccidioidomicose. In: Meira DA (ed) Terapêutica de Doenças Infecciosas e Parasitárias, ( EPUME, Rio de Janeiro p. 175-182, 1987.
19. Motulsky A. Pharmacogenetics. Progress Medical Genetics 3: 49-74, 1964.
20. Moura RAA. Técnicas de laboratório. 2nd. ed. Atheneu, São Paulo, 1982.
21. Organization Mundial de la Salud. Normalización de las técnicas de estudio de la glucosa-6-fosfato deshidrogenasa. Série de Informes Técnicos 366: 1-257, 1967.
22. Padilha-Gonçalves A. Estudo das concentrações sanguíneas das sulfonamidas no decurso do tratamento da blastomicose brasileira. O Hospital 29: 875-881,1946.
23. Paniker NV, Beutler E. The effect of methylene blue and diaminodiphenylsulfone on red cell reduced glutathione synthesis. Journal of Laboratory Clinical Medicine 80: 481-487, 1972.
24. Peters JH, Gordon GR, Brown P. The relationship between the capacities of human subjects to acetylate isoniazid, sulfanilamide and sulfamethazine. Life Sciences 4: 99-107, 1965.
25. Snedecor GW, Cochran WG. Statistical methods. Ames Iowa State University, 1980.
26. Sunahara S, Urano M, Ogawa M. Genetica and geographical studies in isoniazid inactivation. Science 134: 1530-1531, 1961.
27. Vree TB, O'Reilly WJ, Kekster YA, Damsma JE, Van der Kleijin E. Determination of the acetylator phenotype and pharmacokinetics of some sulphonamides in man. Clinical Pharmacokinetics 5: 274-294, 1980.

Adress to correspondence:

Dr. Benedito Barraviera

Faculdade de Medicina de Botucatu/UNESP

CP: 576

18610

Botucatu, SP, Brasil.

Publication Dates

Publication in this collection
15 May 2013
Date of issue
June 1991

History

Accepted
28 Dec 1990
Received
28 Dec 1990

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Barraviera B. Effect of antimalarial drugs and of clindamycin on erythrocyte metabolism. A review. Revista do Instituto de Medicina Tropical de São Paulo 31:200- 205, 1989.

[2] 2. Barraviera B, Machado PEA, Meira DA. Glutathion reductase activity and its relation with riboflavin levels measured by methemoglobin reduction by cystamine in patients with malaria. (Preliminary Report). Revista do Instituto de Medicina Tropical de São 30: 107-108, 1988.

[3] 3. Barraviera B, Machado PEA, Meira DA, Curi PR, Martins JNP, Souza MJ. Glucose-6-phosphate dehydrogenase and glutathione reductase activity in methemoglobin reduction by methylene blue and cystamine. Study on gIucose-6-phosphate dehydrogenase-deficient individuals, on normal subjects and on riboflavin-treated subjects. Revista do Instituto de Medicina Tropical de São Paulo 30: 370-378,1988.

[4] 4. Barraviera B, Meira DA, Machado PEA, Curi PR. Malária no município de Humaitá, Estado do Amazonas XXI. Prevalência da deficiência de glicose-6-fosfato desidrogenase (G6PD) em amostra da população e em doentes com malária causada pelo Plasmodium falciparum . Revista do Institute de Medicina Tropical de São Paulo 29: 374-380,1987.

[5] 5. Barraviera B, Mendes RP, Machado JM, Pereira PCM, Souza MJ, Meira DA. Evaluation of treatment of paracoccidioidomycosis with cotrimazine (combination of sulfadiazine and trimethoprim). Revista do Institute de Medicina Tropical de São Paulo 31: 53-55, 1989.

[6] 6. Barraviera B, Mendes RP, Pereira PCM, Machado JM, Curi PR, Meira DA. Measurement of glucose-6-phosphate dehydrogenase and glutathione reductase activity in patients with paracoccidioidomycosis treated with ketoconazole. Mycopathologia 104: 87-91, 1988.

[7] 7. Barraviera B, Paiva SAR, Marques MEA, Machado JCMS. Paracoccidioidomicose subaguda progressiva. Tratamento de um doente com cotrimoxazole e nutrição parenteral. Arquivos Brasileiros de Medicina 63: 406- 410, 1989.

[8] 8. Barraviera B, Pereira PCM, Mendes RP, Machado JM, Lima CRG, Meira DA. Evaluation of acetylator phenotype, renal function and serum sulfadiazine levels in patients with paracoccidioidomycosis treated with cotrimazine (combination, of sulfadiazine and trimethoprim). Mycopathologia 108: 107-112, 1989.

[9] 9. Barraviera SRCS, Barraviera B, Machado PEA, Habermann MC, Stolf HO, Gonzaga HFS. Uso da riboflavina no tratamento da hemólise pela sulfona em doente com dermatite herpetiforme de Duhring-Brocq deficiente em glutationa redutase. Anais Brasileiros de Dermatologia 64: 231-233, 1989.

[10] 10. BeiguelmanB, Ramalho AS, ArenaJFP, GarlippCR. A acetilação da isoniazida em brasileiros caucasóides e negróides com tuberculose pulmonar. Revista Paulista de Medicina 89: 12-15, 1977.

[11] 11. Bratton AC, Marshall EK. A new coupling component for sulfanilamide. Journal of Biological Chemistry 128: 537-550, 1939.

[12] 12. Eidus L, Varughese P, Hodgkin MM, Hsu AHE, McRae KB. Simplification of isoniazid phenotyping procedure to promote its aplication in the chemoterapy of tuberculosis. Bulletin of the World Health Organization 49:507- 516, 1973.

[13] 13. Franco MF, Montenegro MR, Mendes RP, Marques SA, Dillon NL, Mota NGS. Paracoccidioidomycosis: a recently proposed classification of its clinical forms. Revista da Sociedade Brasileira de Medicina Tropical 20: 129-132, 1987.

[14] 14. Grimes AJ. Human red cell metabolism. Blackwell, London, 1980.

[15] 15. Hodgkin MM, Eidus L, Hamilton EJ. Screening of isoniazid inactivators by dilution test Bulletin of the World Health Organization 51: 428-430, 1974.

[16] 16. Marcondes JM, Meira DA, Machado PEA, Barraviera B, Matsubara LS, Vadileti C, Pirolla JAG, Machado EAB. Malária no município de Humaitá, Estado do 'Amazonas XIV - Inquérito coprológico em habitantes da região em relação às taxas de hemoglobina. Revista do Instituto de Medicina Tropical de São Paulo 24(supl 6): 24-28, 1982.

[17] 17. Martinez R, Meneghelli VG, Fiorillo AM, Oliveira RB. O comprometimento gastrintestinal na blastomicose sul- americana (Paracoccidioidomicose) II. Estudo funcional do intestino delgado. Revista da Associação Médica Brasileira 25: 70-72, 1979.

[18] 18. Mendes RP. Paracoccidioidomicose. In: Meira DA (ed) Terapêutica de Doenças Infecciosas e Parasitárias, ( EPUME, Rio de Janeiro p. 175-182, 1987.

[19] 19. Motulsky A. Pharmacogenetics. Progress Medical Genetics 3: 49-74, 1964.

[20] 20. Moura RAA. Técnicas de laboratório. 2nd. ed. Atheneu, São Paulo, 1982.

[21] 21. Organization Mundial de la Salud. Normalización de las técnicas de estudio de la glucosa-6-fosfato deshidrogenasa. Série de Informes Técnicos 366: 1-257, 1967.

[22] 22. Padilha-Gonçalves A. Estudo das concentrações sanguíneas das sulfonamidas no decurso do tratamento da blastomicose brasileira. O Hospital 29: 875-881,1946.

[23] 23. Paniker NV, Beutler E. The effect of methylene blue and diaminodiphenylsulfone on red cell reduced glutathione synthesis. Journal of Laboratory Clinical Medicine 80: 481-487, 1972.

[24] 24. Peters JH, Gordon GR, Brown P. The relationship between the capacities of human subjects to acetylate isoniazid, sulfanilamide and sulfamethazine. Life Sciences 4: 99-107, 1965.

[25] 25. Snedecor GW, Cochran WG. Statistical methods. Ames Iowa State University, 1980.

[26] 26. Sunahara S, Urano M, Ogawa M. Genetica and geographical studies in isoniazid inactivation. Science 134: 1530-1531, 1961.

[27] 27. Vree TB, O'Reilly WJ, Kekster YA, Damsma JE, Van der Kleijin E. Determination of the acetylator phenotype and pharmacokinetics of some sulphonamides in man. Clinical Pharmacokinetics 5: 274-294, 1980.