Dapsone‐Associated Methemoglobinemia in a Patient With Slow NAT2*5B Haplotype and Impaired Cytochrome b5 Reductase Activity

Abouraya, Mahmoud; Sacco, James C.; Hayes, Kristie; Thomas, Sajeve Samuel; Kitchens, Craig S.; Trepanier, Lauren A.

doi:10.1177/0091270010393343

Cited by 7 publications

(5 citation statements)

References 39 publications

(62 reference statements)

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“…Congenital methemoglobinemia is induced by a deficiency in b5R. However, a very low level of cyt b5/b5R reduction activity was reported in the leukocytes of an acquired methemoglobinemia patient (11). The patient in that study exhibited a low leukocyte messenger RNA (mRNA) expression for CYB5A (which encodes cyt b5) and CYB5R3 (which encodes b5R) compared with healthy controls, consistent with the patient's low reduction activity.…”

Section: Discussionsupporting

confidence: 62%

“…Sulfamethoxazole and dapsone are both arylamine compounds that generate similar hydroxylamine metabolites that lead to adverse drug reactions, and both drugs are metabolized by the N-acetyl transferase 2 (NAT2) and cytochrome b5 (cyt b5)/NADH cytochrome b5 reductase (b5R) pathways (9,10). A case of dapsone-associated methemoglobinemia with an NAT2*5B haplotype has been reported (11). Furthermore, slow NAT2 genotypes have been reported to be risk factors for dose-dependent adverse reactions to sulfasalazine (12).…”

Section: Discussionmentioning

confidence: 99%

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Methemoglobinemia Induced by Trimethoprim-Sulfamethoxazole in a Patient with Systemic Lupus Erythematosus

et al. 2013

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We herein report a case of methemoglobinemia induced by trimethoprim-sulfamethoxazole (TMP/SMX). A 41-year-old woman with systemic lupus erythematosus (SLE) received TMP/SMX for prophylaxis of pneumocystis pneumonia (PCP) on the 7th day of hospitalization. She suddenly developed dyspnea and cyanosis on the 9th day of hospitalization. The level of oxygen saturation (SaO2) decreased, and the concentration of methemoglobin (MetHb) in the blood was elevated. We diagnosed the patient with methemoglobinemia induced by TMP/SMX. Methemoglobinemia should be considered in cases of sudden dyspnea following TMP/ SMX administration.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Methemoglobinemia Induced by Trimethoprim-Sulfamethoxazole in a Patient with Systemic Lupus Erythematosus

et al. 2013

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“…Cytochrome b 5 reductase activities were also evaluated using cytochrome c as a prototype substrate, (Fitzsimmons et al, 1996) with 10 µM dicoumarol included to inhibit competing NAD(P)H:quinone oxidoreductase activity (Abouraya M. et al, 2012). …”

Section: Methodsmentioning

confidence: 99%

Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection

Wong

Rakasz²,

Gasper

et al. 2016

Toxicology

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Background Sulfonamide hypersensitivity has a high incidence in HIV infection and correlates with low CD4+ counts, but the mechanisms are not understood. The aims of this study were to determine whether trimethoprim/sulfamethoxazole (TMP/SMX) led to SMX adduct formation, immunogenicity, or signs of drug hypersensitivity in SIV-infected rhesus macaques, and whether differences in antioxidants, pro-inflammatory mediators, or SMX disposition were predictive of drug immunogenicity. Methods Nine macaques chronically infected with SIVmac239 and 7 non-infected controls were studied. Baseline blood ascorbate, glutathione, IFN-γ, LPS, sCD14, and cytochrome b5 reductase measurements were obtained, macaques were dosed with TMP/SMX (120 mg/kg/day p.o. for 14 days), and SMX metabolites, lymph node drug adducts, drug-responsive T cells, and anti-SMX antibodies were measured. Results Four of 9 of SIV-positive (44%), and 3 of 7 SIV negative (43%) macaques had drug-responsive T cells or antibodies to SMX. Two macaques developed facial or truncal rash; these animals had the highest levels of lymph node drug adducts. Antioxidants, pro-inflammatory mediators, and SMX metabolites were not predictive of drug immunogenicity; however, the Mamu DRB1*0401/0406/0411 genotype was significantly over-represented in immune responders. Conclusions Unlike other animal models, macaques develop an immune response, and possible rash, in response to therapeutic dosages of TMP/SMX. Studying more animals with CD4+ counts < 200 cells/µl, along with moderately restricted ascorbate intake to match deficiencies seen in humans, may better model the risk of SMX hypersensitivity in HIV-infection. In addition, the role of Mamu-DRB1 genotype in modeling drug hypersensitivity in retroviral infection deserves further study.

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“…Other factors within dapsone metabolism that have been linked with increased risk of MHb include polymorphisms within the CYP2 isoenzyme family and cytochrome b5 reductase, which can lead to congenital MHb . Because of the nature of our study, we were not able to look into these risk factors.…”

Section: Discussionmentioning

confidence: 99%

Dapsone‐induced methemoglobinemia in renal transplant recipients: more prevalent than previously thought

Mitsides

Middleton

et al. 2013

Transplant Infectious Dis

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Dapsone‐Associated Methemoglobinemia in a Patient With Slow *NAT2**5B Haplotype and Impaired Cytochrome b₅ Reductase Activity

Cited by 7 publications

References 39 publications

Methemoglobinemia Induced by Trimethoprim-Sulfamethoxazole in a Patient with Systemic Lupus Erythematosus

Methemoglobinemia Induced by Trimethoprim-Sulfamethoxazole in a Patient with Systemic Lupus Erythematosus

Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection

Dapsone‐induced methemoglobinemia in renal transplant recipients: more prevalent than previously thought

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