Regio- and stereoselective propranolol metabolism by 15 forms of purified cytochromes P-450 from rat liver.
Regio- and stereoselectivity of cytochrome P-450-mediated propranolol metabolism (4-, 5- and 7-hydroxylations and N-desisopropylation) was studied using 15 purified cytochrome P-450 species. With each purified cytochrome P-450 species, the regioselectivity was distinct and different between the two optical isomers used as substrates. The stereoselectivity was different depending on the position of propranolol to be metabolized. The regio- and stereoselectivity was altered when substrate concentration was altered, suggesting that the kinetics of the reactions are different depending on the positions of propranolol to be metabolized. Furthermore, the selectivity and its manner of alterations with substrate concentrations were different among all cytochrome P-450 species used. Propranolol, with its multiple metabolic pathways and optical isomers, is an extremely interesting substrate for characterization of cytochrome P-450 species.
Fujita
S
S
Department of Toxicology, Faculty of Veterinary Medicine, Sapporo, Japan.
Umeda
S
S
Funae
Y
Y
Imaoka
S
S
Abe
H
H
Ishida
R
R
Adachi
T
T
Masuda
M
M
Kazusaka
A
A
Suzuki
T
T
D000595:Amino Acid Sequence; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification / Q000378:metabolism*; D006900:Hydroxylation; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008969:Molecular Sequence Data; D011433:Propranolol / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013237:Stereoisomerism
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D006899:Mixed Function Oxygenases