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Regioselective Versatility of Monooxygenase Reactions Catalyzed by CYP2B6 and CYP3A4: Examples with Single Substrates

  • Chapter
Book cover Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 851))

Abstract

Hepatic microsomal cytochrome P450 (CYP) enzymes have broad and overlapping substrate specificity and catalyze a variety of monooxygenase reactions, including aliphatic and aromatic hydroxylations, N-hydroxylations, oxygenations of heteroatoms (N, S, P and I), alkene and arene epoxidations, dehalogenations, dehydrogenations and N-, O- and S-dealkylations. Individual CYP enzymes typically catalyze the oxidative metabolism of a common substrate in a regioselective and stereoselective manner. In addition, different CYP enzymes often utilize different monooxygenase reactions when oxidizing a common substrate. This review examines various oxidative reactions catalyzed by a CYP enzyme acting on a single substrate. In the first example, 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a halogenated aromatic environmental contaminant, was oxidatively biotransformed by human CYP2B6. Nine different metabolites of BDE-47 were produced by CYP2B6 via monooxygenase reactions that included aromatic hydroxylation, with and without an NIH-shift, dealkylation and debromination. In the second example, lithocholic acid (3α-hydroxy-5β-cholan-24-oic acid), an endogenous bile acid, served as a substrate for human CYP3A4 and yielded five different metabolites via aliphatic hydroxylation and dehydrogenation reactions.

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Notes

  1. 1.

    Abbreviations: BDE-47 2,2′,4,4′-tetrabromodiphenyl ether, BDE-99 2,2′,4,4′,5-pentabromodiphenyl ether, CAR constitutive androstane receptor, CYP cytochrome P450, lithocholic acid 3α-hydroxy-5β-cholan-24-oic acid, PBDEs polybrominated diphenyl ethers, PXR pregnane X receptor, QSAR quantitative structure-activity relationship.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, V6T1Z3, Canada

    Claudio A. Erratico, Anand K. Deo & Stelvio M. Bandiera

  2. Toxicology Center, University of Antwerp, Wilrijk, 2610, Belgium

    Claudio A. Erratico

  3. UCB Pharma, Briane l’Alleud, 1420, Belgium

    Anand K. Deo

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  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Eugene G. Hrycay

  2. Fac. of Pharmaceutical Sciences, The University of British Columbia , Vancouver, British Columbia, Canada

    Stelvio M. Bandiera

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Erratico, C.A., Deo, A.K., Bandiera, S.M. (2015). Regioselective Versatility of Monooxygenase Reactions Catalyzed by CYP2B6 and CYP3A4: Examples with Single Substrates. In: Hrycay, E., Bandiera, S. (eds) Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450. Advances in Experimental Medicine and Biology, vol 851. Springer, Cham. https://doi.org/10.1007/978-3-319-16009-2_5

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