Stereoselectivity in the oxidation of bufuralol, a chiral substrate, by human cytochrome P450s.
Bufuralol (BF), a nonselective beta-adrenoceptor blocking agent, has a chiral center in its molecule, yielding the enantiomers 1'R-BF and 1'S-BF. beta-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 beta-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.
Narimatsu
Shizuo
S
Laboratory of Health Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan. shizuo@pharm.okayama-u.ac.jp
Takemi
Chie
C
Kuramoto
Shino
S
Tsuzuki
Daisuke
D
Hichiya
Hiroyuki
H
Tamagake
Keietsu
K
Yamamoto
Shigeo
S
D000319:Adrenergic beta-Antagonists / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004983:Ethanolamines / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D011994:Recombinant Proteins; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6