REGIO- AND STEREOSELECTIVITY IN PROPRANOLOL METABOLISM BY DOG LIVER-MICROSOMES AND THE EXPRESSED DOG CYP2D15

We have studied the regio-and stereoselectivity of ring-hydroxylation and N-desisopropylation of S(-)- and R(S)-propranolol, using dog liver microsomes and the expressed dog CYP2D15 in insect cells, In dog live r microsomes, 4-hydroxylation was the preferred pathway in S(-)-propra nolol oxidation, while N-desisopropylation was the preferred pathway i n R(+)-propranolol oxidation, S(-)-Propranolol was preferred over R(+) -propranolol as substrate for 4- and 5-hydroxylations, while R(+)-prop ranolol was the preferred substrate for N-desisopropylation at higher substrate concentrations, The expressed CYP2D15 had high catalytic act ivities toward 4-, B-hydroxylation, as well as N-desisopropylation of both enantiomers. At the substrate concentrations used, 4-hydroxylatio n was the preferred pathway for the metabolism of both enantiomers, an d S(-)-propranolol was the preferred substrate over R(+)-propranolol f or all three monooxygenations catalyzed by CYP2D15. Anti-CYP2D15 pepti de antibody strongly inhibited 4- and 5-hydroxylation of both enantiom ers in dog liver microsomes, while it did not inhibit their N-desisopr opylation, These findings suggest that CYP2D15 is highly responsible f or the stereoselective 4- and 5-hydroxylations of propranolol in dog l iver microsomes.