Myeloperoxidase-mediated activation of xenobiotics by human leukocytes

Hofstra, Angela H.; Uetrecht, Jack

doi:10.1016/0300-483x(93)90066-2

Cited by 43 publications

(34 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Leukocytes are recruited in immune response and therefore, reactive intermediates from xenobiotics generated by leukocyte metabolism may play a role in idiosyncratic drug reactions. 5,6 Various drugs, but also arylamines and benz[a]pyrene from tobacco smoke are converted to cytotoxic products. The degranulation of these cells and also their hyperactive state in the presence of chronic antigenic stimulation may transform environmental pre-carcinogens to highly reactive intermediates 7 as was shown for heterocyclic amine activation by MPO in fibroblasts and epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Gender and smoking-related risk reduction of periodontal disease with variant myeloperoxidase alleles

et al. 2002

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

Gender and smoking-related risk reduction of periodontal disease with variant myeloperoxidase alleles

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Myeloperoxidase-catalyzed oxidations have been implicated in the toxicity of other drugs such as clozapine (Hofstra and Uetrecht, 1993;Ip and Uetrecht, 2006). The conversion of nomifensine to the dihydroisoquinolinium ion by myeloperoxidase was stimulated by acetaminophen.…”

Section: Discussionmentioning

confidence: 96%

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

View full text Add to dashboard Cite

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.

show abstract

“…The enzyme myeloperoxidase (MPO) appears to be the most important in the metabolic activation of drugs to RMs. MPO is a peroxidase and generates the powerful oxidant hypochlorous acid, which is capable of oxidizing a broad range of electron-rich functional groups, especially those that contain oxygen, sulfur, and nitrogen (Hofstra and Uetrecht, 1993).…”

Section: Perspectivementioning

confidence: 99%

Immune-Mediated Agranulocytosis Caused by the Cocaine Adulterant Levamisole: A Case for Reactive Metabolite(s) Involvement

Wolford

McDonald²,

Eng³

et al. 2012

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The United States Public Health Service Administration is alerting medical professionals that a substantial percentage of cocaine imported into the United States is adulterated with levamisole, a veterinary pharmaceutical that can cause blood cell disorders such as severe neutropenia and agranulocytosis. Levamisole was previously approved in combination with fluorouracil for the treatment of colon cancer; however, the drug was withdrawn from the U.S. market in 2000 because of the frequent occurrence of agranulocytosis. The detection of autoantibodies such as antithrombin (lupus anticoagulant) and an increased risk of agranulocytosis in patients carrying the human leukocyte antigen B27 genotype suggest that toxicity is immune-mediated. In this perspective, we provide an historical account of the levamisole/cocaine story as it first surfaced in 2008, including a succinct review of levamisole pharmacology, pharmacokinetics, and preclinical/clinical evidence for levamisole-induced agranulocytosis. Based on the available information on levamisole metabolism in humans, we propose that reactive metabolite formation is the rate-limiting step in the etiology of agranulocytosis associated with levamisole, in a manner similar to other drugs (e.g., propylthiouracil, methimazole, captopril, etc.) associated with blood dyscrasias. Finally, considering the toxicity associated with levamisole, we propose that the 2,3,5,6-tetrahydroimidazo[2,1-b]thiazole scaffold found in levamisole be categorized as a new structural alert, which is to be avoided in drug design.

show abstract

Myeloperoxidase-mediated activation of xenobiotics by human leukocytes

Cited by 43 publications

References 81 publications

Gender and smoking-related risk reduction of periodontal disease with variant myeloperoxidase alleles

Gender and smoking-related risk reduction of periodontal disease with variant myeloperoxidase alleles

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

Immune-Mediated Agranulocytosis Caused by the Cocaine Adulterant Levamisole: A Case for Reactive Metabolite(s) Involvement

Contact Info

Product

Resources

About