title: CYP3A-mediated generation of aldehyde and hydrazine in atazanavir metabolism.
abstract: Atazanavir (ATV) is an antiretroviral drug of the protease inhibitor class. Multiple adverse effects of ATV have been reported in clinical practice, such as jaundice, nausea, abdominal pain, and headache. The exact mechanisms of ATV-related adverse effects are unknown. It is generally accepted that a predominant pathway of drug-induced toxicity is through the generation of reactive metabolites. Our current study was designed to explore reactive metabolites of ATV. We used a metabolomic approach to profile ATV metabolism in mice and human liver microsomes. We identified 5 known and 13 novel ATV metabolites. Three potential reactive metabolites were detected and characterized for the first time: one aromatic aldehyde, one α-hydroxyaldehyde, and one hydrazine. These potential reactive metabolites were primarily generated by CYP3A. Our results provide a clue for studies on ATV-related adverse effects from the aspect of metabolic activation. Further studies are suggested to illustrate the impact of these potential reactive metabolites on ATV-related adverse effects.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Laiyou
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
mesh_terms: D000447:Aldehydes / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D000818:Animals; D000069446:Atazanavir Sulfate; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D006834:Hydrazines / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D007654:Ketoconazole / Q000494:pharmacology; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D011725:Pyridines / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D011994:Recombinant Proteins / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D000447:Aldehydes; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D006834:Hydrazines; D009842:Oligopeptides; D011725:Pyridines; D011994:Recombinant Proteins; D000069446:Atazanavir Sulfate; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole