title: CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems.
abstract: Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 μl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo.
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.
authors: Zhexue
authors: Z
authors: Wu
authors: Doohyun
authors: D
authors: Lee
authors: Jeongmin
authors: J
authors: Joo
authors: Jung-Hoon
authors: JH
authors: Shin
authors: Wonku
authors: W
authors: Kang
authors: Sangtaek
authors: S
authors: Oh
authors: Do Yup
authors: DY
authors: Lee
authors: Su-Jun
authors: SJ
authors: Lee
authors: Sung Su
authors: SS
authors: Yea
authors: Hye Suk
authors: HS
authors: Lee
authors: Taeho
authors: T
authors: Lee
authors: Kwang-Hyeon
authors: KH
authors: Liu
mesh_terms: D015766:Albendazole / Q000378:metabolism*; D000871:Anthelmintics / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D065731:Cytochrome P-450 CYP2C19; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005273:Fenbendazole / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000871:Anthelmintics; C000717350:CYP2J2 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D005273:Fenbendazole; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000090762:Cytochrome P-450 CYP2J2; D015766:Albendazole
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