Development of dapsone toxicity in patients with inflammatory dermatoses: Activity of acetylation and hydroxylation of dapsone as risk factors

Bluhm, Ranata E.; Adedoyin, Adedayo; McCarver, D. Gail; Branch, Robert A.

doi:10.1016/s0009-9236(99)90081-4

Cited by 57 publications

(41 citation statements)

References 25 publications

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“…Production of dapsone hydroxylamine is thought to be responsible for the hematological toxicity (especially methemoglobinemia) of dapsone (Israili et al, 1973;Coleman et al, 1989;Gill et al, 1995). A recent study reported more severe adverse reactions (anemia or neurotoxicity) in individuals who were both slow acetylators and rapid hydroxylators (Bluhm et al, 1999), presumably because more dapsone is metabolized via the detrimental hydroxylamine pathway rather than by acetylation. Overall, it seems unlikely that knowledge of acetylator status will assist with dosing of this drug.…”

Section: A Acetyltransferasementioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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Section: A Acetyltransferasementioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…117 The most severe incidence of toxicity occurred in individuals with a slow acetylator phenotype who are rapid hydroxylators, which is consistent with the role each pathway has in the activation and detoxification of the drug. 118 While slow acetylators are at a greater risk of toxicity from sulphonamides and dapsone, other therapeutic agents exhibit increased incidence of adverse reactions in rapid acetylators. Amonafide is a novel arylamine that has previously been used in clinical trials for the treatment of various cancers.…”

Section: Nat and Drug Responsementioning

confidence: 99%

Pharmacogenetics of the arylamine N-acetyltransferases

et al. 2002

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The arylamine N-acetyltransferases (NATs) are involved in the metabolism of a variety of different compounds that we are exposed to on a daily basis. Many drugs and chemicals found in the environment, such as those in cigarette smoke, car exhaust fumes and in foodstuffs, can be either detoxified by NATs and eliminated from the body or bioactivated to metabolites that have the potential to cause toxicity and/or cancer. NATs have been implicated in some adverse drug reactions and as risk factors for several different types of cancers. As a result, the levels of NATs in the body have important consequences with regard to an individual's susceptibility to certain druginduced toxicities and cancers. This review focuses on recent advances in the molecular genetics of the human NATs.

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“…Initiation of this adverse effect could arise via the generation of a reactive metabolite, but proof of such an intermediate for nomifensine has not been reported, despite demonstration of nomifensine antibodies in patients Mueller-Eckhardt, 1985, 1986). Nomifensine is an aromatic amine, and compounds containing aromatic amines such as dapsone have been shown to be associated with blood and liver toxicities (Bluhm et al, 1999;Kalgutkar et al, 2005). Also, a methyl catechol metabolite of nomifensine was demonstrated in humans, suggesting the possible presence of a catechol intermediate metabolite that could be the precursor of an electrophilic ortho-quinone.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Nomifensine to a Dihydroisoquinolinium Ion Metabolite by Human Myeloperoxidase, Hemoglobin, Monoamine Oxidase A, and Cytochrome P450 Enzymes

Obach¹,

Dalvie²

2006

Drug Metab Dispos

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ABSTRACT:Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, we demonstrate the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H 2 O 2 . Human myeloperoxidase catalyzed this reaction in the presence of H 2 O 2 , and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7. The dihydroisoquinolinium ion was shown to react with cyanide and borohydride, but not glutathione. These findings suggest that the electrophilic nomifensine dihydroisoquinolinium metabolite, which can be generated by several enzymes, could be behind toxic responses to nomifensine such as hemolytic anemia and hepatotoxicity.

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Development of dapsone toxicity in patients with inflammatory dermatoses: Activity of acetylation and hydroxylation of dapsone as risk factors

Cited by 57 publications

References 25 publications

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Pharmacogenetics of the arylamine N-acetyltransferases

Metabolism of Nomifensine to a Dihydroisoquinolinium Ion Metabolite by Human Myeloperoxidase, Hemoglobin, Monoamine Oxidase A, and Cytochrome P450 Enzymes

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