Horseradish peroxidase-catalyzed oxidation of rifampicin: reaction rate enhancement by co-oxidation with anti-inflammatory drugs.
The tuberculostatic drug rifampicin has been described as a scavenger of reactive species. Additionally, the recent demonstration that oral therapy with a complex of rifampicin and horseradish peroxidase (HRP) was more effective than rifampicin alone, in an animal model of experimental leprosy, suggested the importance of redox reactions involving rifampicin and their relevance to the mechanism of action. Hence, we studied the oxidation of rifampicin catalyzed by HRP, since this enzyme may represent the prototype of peroxidation-mediated reactions. We found that the antibiotic is efficiently oxidized and that rifampicin-quinone is the product, in a reaction dependent on both HRP and hydrogen peroxide. The steady-state kinetic constants Km(app) (101+/-23 micromol/l), Vmax(app) (0.78+/-0.09 micromol/l.s(-1)) and kcat (5.1+/-0.6 s(-1)) were measured (n=4). The reaction rate was increased by the addition of co-substrates such as tetramethylbenzidine, salicylic acid, 5-aminosalicylic acid and paracetamol. This effect was explained by invoking an electron-transfer mechanism by which these drugs acted as mediators of rifampicin oxidation. We suggested that this drug interaction might be important at the inflammatory site.
dos Santos
Fernanda de Jesus Notário
Fde J
Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, UNESP - São Paulo State University; Brasil.
Ximenes
Valdecir Farias
VF
da Fonseca
Luiz Marcos
LM
de Faria Oliveira
Olga Maria Mascarenhas
OM
Brunetti
Iguatemy Lourenço
IL
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D002384:Catalysis; D006735:Horseradish Peroxidase / Q000378:metabolism*; D010084:Oxidation-Reduction; D012293:Rifampin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000995:Antitubercular Agents; D006735:Horseradish Peroxidase; D012293:Rifampin