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First published on September 22, 2006; DOI: 10.1124/dmd.106.010587

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Received for publication April 24, 2006.
Revised September 20, 2006.
Accepted for publication September 21, 2006.

CYP4F ENZYMES ARE THE MAJOR ENZYMES IN HUMAN LIVER MICROSOMES THAT CATALYZE THE O-DEMETHYLATION OF THE ANTIPARASITIC PRODRUG DB289

Michael Zhuo Wang 1, Janelle Y Saulter 1, Etsuko Usuki 2, Yen-Ling Cheung 3, Michael Hall 3, Arlene S Bridges 1, Greg Loewen 2, Oliver T Parkinson 2, Chad E Stephens 4, James L Allen 5, Darryl C Zeldin 6, David W Boykin 4, Richard R Tidwell 1, Andrew Parkinson 2, Mary F Paine 1, James Edwin Hall 1*

1 The University of North Carolina at Chapel Hill 2 XenoTech LLC 3 Huntingdon Life Sciences Ltd. 4 Georgia State University 5 Immtech Pharmaceuticals Inc. 6 NIEHS/NIH

* Address correspondence to: E-mail: je_hall{at}unc.edu

Abstract

DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime] is biotransformed to the potent antiparasitic diamidine DB75 [2,5-bis(4-amidinophenyl) furan] by sequential oxidative O-demethylation and reductive N-dehydroxylation reactions. Previous work demonstrated that the N-dehydroxylation reactions are catalyzed by cytochrome b5/NADH b5 reductase. Enzymes responsible for catalyzing the DB289 O-demethylation pathway have not been identified. We report an in vitro metabolism study to characterize enzymes in human liver microsomes (HLM) that catalyze the initial O-demethylation of DB289 (M1 formation). Potent inhibition by 1-aminobenzotriazole confirmed that M1 formation is catalyzed by CYP enzymes. M1 formation by HLM was NADPH-dependent, with a Km and Vmax of 0.5 µM and 3.8 nmol/min/mg protein, respectively. Initial screening showed that recombinant CYP1A1, CYP1A2, and CYP1B1 were efficient catalysts of M1 formation. However, none of these three enzymes was responsible for M1 formation by HLM. Further screening showed that recombinant CYP2J2, CYP4F2, and CYP4F3B could also catalyze M1 formation. An antibody against CYP4F2, which inhibited both CYP4F2 and CYP4F3B, inhibited 91% of M1 formation by HLM. Two inhibitors of CYP-mediated arachidonic acid metabolism, HET0016 and 17-ODYA, effectively inhibited M1 formation by HLM. Inhibition studies with ebastine and antibodies against CYP2J2 suggested that CYP2J2 was not involved in M1 formation by HLM. Additionally, ketoconazole preferentially inhibited CYP4F2, but not CYP4F3B, and partially inhibited M1 formation by HLM. We conclude that CYP4F enzymes (e.g., CYP4F2, CYP4F3B) are the major enzymes responsible for M1 formation by HLM. These findings indicate that, in human liver, members of the CYP4F subfamily not only biotransform endogenous compounds, but also xenobiotics.


Key words: bioactivation, CYP4, enzyme inhibitors, enzyme kinetics, first-pass metabolism, human CYP enzymes, liver microsomes, prodrugs


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