Involvement of a cytochrome P4502D subfamily in human liver microsomal bunitrolol 4-hydroxylation.
The oxidative metabolism of bunitrolol, an adrenergic beta-receptor antagonist was examined in human liver microsomes fortified with an NADPH-generating system. The microsomal fractions (n = 11) showed bunitrolol 4-hydroxylase activities, which correlated well with CYP2D6 contents (correlation coefficient, r = 0.854), debrisoquine 4-hydroxylase (r = 0.953) and imipramine 2-hydroxylase (r = 0.976) activities. On the other hand, the bunitrolol 4-hydroxylase activity showed relatively poor correlations with CYP3A4 content (r = 0.552) and testosterone 6 beta-hydroxylase activity (r = 0.668). The bunitrolol 4-hydroxylase activity was significantly inhibited by quinidine, a selective inhibitor for CYP2D6. Polyclonal antibodies raised against rat liver microsomal cytochrome P450BTL, which is thought to belong to the CYP2D subfamily, effectively inhibited bunitrolol 4-hydroxylation. In contrast, polyclonal antibodies raised against human liver microsomal CYP3A4 did not show any inhibitory effect on the activity. These results suggest that CYP2D6 is involved in the bunitrolol 4-hydroxylase activity in human liver microsomes.
Narimatsu
S
S
Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Masubuchi
Y
Y
Hosokawa
S
S
Ohmori
S
S
Kitada
M
M
Suzuki
T
T
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009249:NADP / Q000494:pharmacology; D010084:Oxidation-Reduction; D011412:Propanolamines / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D065607:Cytochrome P-450 Enzyme Inhibitors; D011412:Propanolamines; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; C510163:CYP3A4 protein, human; C071864:bunitrolol 4-hydroxylase; C084811:bunitrolol; D011802:Quinidine