title: Identification of the human liver cytochrome P450 isoenzymes responsible for the 5-methylhydroxylation of the novel anti-fibrotic drug AKF-PD.
abstract: Identification of cytochrome P450 isoforms (CYPs) involved in flourofenidone (5-methyl-1-(3-fluorophenyl)-2-[1H]-pyridone, AKF-PD) 5-methylhydroxylation was carried out using human liver microsomes and cDNA-expressed human CYPs (supersomes). The experiments were performed in the following in vitro models: (A) a study of AKF-PD metabolism in liver microsomes: (a) correlations study between the rate of AKF-PD 5-methylhydroxylation and activity of CYPs; (b) the effect of specific CYPs inhibitors on the rate of AKF-PD 5-methylhydroxylation; (B) AKF-PD biotransformation by cDNA-expressed human CYPs (1A2, 2D6, 2C9, 2C19, 2E1, 3A4). In human liver microsomes, the formation of AKF-PD 5-methylhydroxylation metabolite significantly correlated with the caffeine N3-demethylase (CYP1A2), chlorzoxazone 6-hydroxylase (CYP2E1), midazolam 1'- hydroxylase (CYP3A4), tolbutamide 4-hydroxylase (CYP2C9), and debrisoquin 4-hydroxylase (CYP2D6) activities. The production of AKF-PD 5-methylhydroxylation metabolite was completely inhibited by a-naphthoflavone (a CYP1A2 inhibitor) with the IC50 value of 0.12 μM in human liver microsomes. The cDNA-expressed human CYPs generated different amounts of AKF-PD 5-methylhydroxylation metabolites, but the preference of CYP isoforms to catalyze AKF-PD metabolism was as follows: 2D6 > 2C19 > 1A2 > 2E1 > 2C9 > 3A4. The results demonstrated that CYP1A2 is the main isoform catalyzing AKF-PD 5-methylhydroxylation while CYP3A4, CYP2C9, CYP2E1, CYP2C19, and CYP2D6 are engaged to a lesser degree. Potential drug-drug interactions involving CYP1A2 may be noticed when AKF-PD is used combined with CYP1A2 inducers or inhibitors.
authors.affiliation: Haikou People's Hospital and Affiliated Haikou Hospital of Xiangya Medical School, Central South University, Haikou, Hainan, PR China.
authors.forename: Xiaoai
authors.initials: X
authors.lastname: He
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Gaoyun
authors.initials: G
authors.lastname: Hu
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Cheng
mesh_terms: D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism*
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D007527:Isoenzymes; D011728:Pyridones; D003577:Cytochrome P-450 Enzyme System; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2