Stereoselective metabolism of bufuralol racemate and enantiomers in human liver microsomes.
A new HPLC method was developed using a chiral column to efficiently separate four 1"-hydroxybufuralol (1"-OH-BF) diastereomers that are major metabolites of bufuralol (BF). Employing this method, we examined diastereomer selectivity in the formation of 1"-OH-BF from BF racemate or enantiomers in four individual samples of human liver microsomes. Three different human liver microsomes showed a selectivity of 1"R-OH < 1"S-OH for BF enantiomers, which was similar to that of recombinant CYP2D6 expressed in insect cell microsomes, whereas one human liver microsomal fraction yielded a selectivity of 1"R-OH > 1"S-OH for BF enantiomers, which was similar to those of recombinant CYP2C19 expressed in insect cell microsomes. Recombinant CYP1A2 and CYP3A4 showed a selectivity similar to that of CYP2D6, but their BF 1"-hydroxylase activities were much lower than those of CYP2D6. In inhibition studies, quinidine, a known CYP2D6 inhibitor, markedly inhibited BF 1"-hydroxylation in the fractions of human liver microsomes that showed the CYP2D6-type selectivity. Furthermore, omeprazole, a known CYP2C19 inhibitor, efficiently suppressed the formation of 1"-OH-BF diastereomers from BF in the microsomal fraction that showed the CYP2C19-type selectivity. From these results, we concluded that the diastereomer selectivity in the formation of 1"-OH-BF from BF differs between CYP2D6 and CYP2C19, both of which can be determinant enzymes in the diastereoselective 1"-hydroxylation of BF in human liver microsomes.
Narimatsu
Shizuo
S
Laboratory of Health Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, Japan. shizuo@pharm.okayama-u.ac.jp
Takemi
Chie
C
Tsuzuki
Daisuke
D
Kataoka
Hiroyuki
H
Yamamoto
Shigeo
S
Shimada
Noriaki
N
Suzuki
Satoshi
S
Satoh
Tetsuo
T
Meyer
Urs A
UA
Gonzalez
Frank J
FJ
D000328:Adult; D000368:Aged; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004983:Ethanolamines / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D013237:Stereoisomerism; D014481:United States; D044465:White People
D004983:Ethanolamines; D007527:Isoenzymes; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System