TY - JOUR
T1 - Stereoselective metabolism of bufuralol racemate and enantiomers in human liver microsomes
AU - Narimatsu, Shizuo
AU - Takemi, Chie
AU - Tsuzuki, Daisuke
AU - Kataoka, Hiroyuki
AU - Yamamoto, Shigeo
AU - Shimada, Noriaki
AU - Suzuki, Satoshi
AU - Satoh, Tetsuo
AU - Meyer, Urs A.
AU - Gonzalez, Frank J.
PY - 2002/10/1
Y1 - 2002/10/1
N2 - 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.
AB - 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.
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U2 - 10.1124/jpet.102.036533
DO - 10.1124/jpet.102.036533
M3 - Article
C2 - 12235248
AN - SCOPUS:0036784537
SN - 0022-3565
VL - 303
SP - 172
EP - 178
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -