title: Role of CYP3A in isoniazid metabolism in vivo.
abstract: Isoniazid (INH), a first-line drug for tuberculosis control, frequently causes liver injury. Multiple previous reports suggest that CYP3A is involved in INH metabolism, bioactivation and hepatotoxicity, although direct evidence is unavailable. In the current study, wild-type and Cyp3a-null mice were used to determine the potential role of Cyp3a in INH metabolism in vivo. Compared to wild-type mice, there were no significant differences in the pharmacokinetic profiles of INH or acetyl-isoniazid in Cyp3a-null mice after an oral administration of 50 mg/kg INH. With the same treatment, distribution of INH and its major metabolites was similar in the liver of wild-type and Cyp3a-null mice. A reactive metabolite of INH was trapped by N-α-acetyl-L-lysine in mouse liver microsomes, but Cyp3a does not contribute to this bioactivation pathway. In addition, no liver injury was observed in wild-type or Cyp3a-null mice treated with 60 or 120 mg/kg INH. In summary, Cyp3a has no effect on systemic pharmacokinetics of INH in mice. Further studies are needed to determine whether and how exactly CYP3A is involved in INH bioactivation and hepatotoxicity.
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Gao
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007538:Isoniazid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D008099:Liver / Q000201:enzymology*; D008297:Male; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology; D008565:Membrane Proteins
chemical_list: D000995:Antitubercular Agents; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D007538:Isoniazid; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins