title: Regioselective Versatility of Monooxygenase Reactions Catalyzed by CYP2B6 and CYP3A4: Examples with Single Substrates.
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.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, V6T1Z3, Canada.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Erratico
authors.forename: Anand K
authors.initials: AK
authors.lastname: Deo
authors.forename: Stelvio M
authors.initials: SM
authors.lastname: Bandiera
mesh_terms: D000818:Animals; D002384:Catalysis; D065702:Cytochrome P-450 CYP2B6 / Q000737:chemistry* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000378:metabolism; D055768:Halogenated Diphenyl Ethers / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008095:Lithocholic Acid / Q000737:chemistry* / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D013379:Substrate Specificity
chemical_list: D055768:Halogenated Diphenyl Ethers; C511295:2,2',4,4'-tetrabromodiphenyl ether; D008095:Lithocholic Acid; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human