Activation of propranolol and irreversible binding to rat liver microsomes: strain differences and effects of inhibitors.
In summary, strain difference and inhibition studies showed that an enzyme(s) converting propranolol to a reactive metabolite capable of irreversible binding to microsomal macromolecules appeared to be a P450 isozyme(s) which catalyses debrisoquine 4-hydroxylation in rats. It seems likely that cytochrome P450 isozymes responsible for debrisoquine 4-hydroxylation activate propranolol and may be impaired after chronic use of propranolol also in human subjects. The findings obtained in the present study provide a clue for the elucidation of the mechanism of propranolol-induced impairment of the drug metabolizing enzyme system. Further studies using purified debrisoquine 4-hydroxylase are required to identify a P450 isozyme(s) responsible for the metabolic activation of propranolol. We are now performing experiments along this line.
Masubuchi
Y
Y
Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Narimatsu
S
S
Suzuki
T
T
D000818:Animals; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6; D042926:Cytochrome P-450 CYP4A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D042926:Cytochrome P-450 CYP4A