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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

The oxidative metabolism of hydralazine by rat liver microsomes.

Previous observations have demonstrated a relationship between the toxicity of the antihypertensive drug, hydralazine (HP), and acetylator phenotype, suggesting a role for metabolism in the adverse effects of HP. Experiments were done to characterize the metabolism of HP by rat liver microsomes using a newly developed HPLC assay. HP was metabolized by rat liver microsomes to products identified by HPLC and mass spectroscopy as s-triazolo[3,4-a]phthalazine (TP), 3-methyl-s-triazolo[3,4-a]phthalazine (MTP), phthalazine ( P), and phthalazinone (PZ). An unknown metabolite was also formed. P, PZ, and the unknown metabolite were established as oxidation products of HP using the model oxidative systems, metal-catalyzed autooxidation and horseradish peroxidase. The results of incubations with [14C]HP indicated that P and the unknown metabolite were quantitatively the major metabolites and were produced in similar quantities by rat liver microsomes. The structure of the unknown metabolite based on mass spectral analyses is proposed to be a dimerization product consisting of P and 1-aminophthalazine. Production of all the microsomal metabolites, except TP, required NADPH and decreased when incubations were done with heat-treated microsomes or under an atmosphere of nitrogen or carbon monoxide. Pretreatment of rats with phenobarbital increased the rate of formation of all the metabolites except TP. In contrast, pretreatment with 3-methylcholanthrene or Arochlor 1254 had no effect on P, PZ, TP, or MTP formation and decreased formation of the dimer. Pretreatment with piperonyl butoxide had no effect on the formation of P, PZ, TP, or MTP but decreased formation of the dimer by approximately 50%.(ABSTRACT TRUNCATED AT 250 WORDS)[1]


  1. The oxidative metabolism of hydralazine by rat liver microsomes. LaCagnin, L.B., Colby, H.D., O'Donnell, J.P. Drug Metab. Dispos. (1986) [Pubmed]
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