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Stereoselectivity in the oxidation of bufuralol, a chiral substrate, by human cytochrome P450s
Author(s) -
Narimatsu Shizuo,
Takemi Chie,
Kuramoto Shino,
Tsuzuki Daisuke,
Hichiya Hiroyuki,
Tamagake Keietsu,
Yamamoto Shigeo
Publication year - 2003
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.10212
Subject(s) - chemistry , hydroxylation , stereochemistry , enantiomer , diastereomer , metabolite , stereoselectivity , cyp1a2 , stereoisomerism , cytochrome p450 , enzyme , molecule , biochemistry , organic chemistry , catalysis
Bufuralol (BF), a nonselective β‐adrenoceptor blocking agent, has a chiral center in its molecule, yielding the enantiomers 1′ R ‐BF and 1′ S ‐BF. β‐Adrenoceptor blocking potency is much higher in 1′ S ‐BF than in 1′ R ‐BF. One of the metabolic pathways of BF is 1″‐hydroxylation of an ethyl group attached at the aromatic 7‐position forming a carbinol metabolite (1″‐hydroxybufuralol, 1″‐OH‐BF), and further oxidation (or dehydrogenation) produces a ketone metabolite (1‐oxobufuralol, 1″‐Oxo‐BF). Both 1″‐OH‐BF and 1″‐Oxo‐BF are known to have β‐adrenoceptor blocking activities comparable to or higher than those of the parent drug. The 1″‐hydroxylation introduces another chiral center into the BF molecule and four 1″‐OH‐BF diastereomers are formed from BF racemate in mammals, including humans, making elucidation of the metabolic profiles complicated. HPLC methods employing derivatization, reversed phase, or chiral columns have been developed to efficiently separate the four 1″‐OH‐BF diastereomers formed from BF enantiomers or racemate. Accumulated in vitro experimental results revealed that 1′ R ‐BF is a much more preferential substrate than 1′ S ‐BR for BF 1″‐hydroxylation in human liver microsomes. Kinetic studies using recombinant human cytochrome P450 (CYP) enzymes indicate that CYP2D6 serves as a major BF 1″‐hydroxylase and that CYP1A2 and CYP2C19 also contribute to BF 1″‐hydroxylation in human livers. This mini‐review summarizes the knowledge reported so far on the pharmacology of BF and its metabolites and the profiles of BF metabolism, especially focusing on the stereoselectivity in the oxidation of BF mainly in human livers and recombinant CYP enzymes. Chirality 15:333–339, 2003. © 2003 Wiley‐Liss, Inc.