Enantioselective N-acetylation of N-desisopropylpropranolol by rat liver acetyltransferase.
The enantioselective N-acetylation of N-desisopropylpropranolol (NDP), one of the main metabolites of propranolol (PL), by rat liver acetyltransferase (AT), was investigated. R(+)-NDP or S(-)-NDP was used as a substrate at concentrations ranging from 10 to 200 microM. The cytosol fraction of a rat liver containing 3.93 mg protein/ml served as the source of AT. For 1-amino-3-(1-naphthyloxy)-2-propanol (AcNDP) formation from R(+)-NDP or S(-)-NDP in the presence of infinite AcCoA (250 microM), the Km value was calculated to be 67.5 or 62.4 microM, and the Vmax value was 0.462 or 0.205 nmol/min/mg protein. Based on these findings, the enantioselective N-acetylation of NDP was proved, i.e., AcNDP formation from R(+)-NDP was found to take place more easily than that from S(-)-NDP. Furthermore, AcNDP formation from NDP was competitively inhibited by the exogenous arylamine, p-aminobenzoic acid (PABA), which is well-known to be a typical substrate of AT. The presence of enantioselective inhibition for AcNDP formation was thus confirmed based on the Ki values, 440 microM in the case of R(+)-NDP and 250 microM in the case of S(-)-NDP, respectively, i.e. two-fold enantioselective inhibition was demonstrated based on the Ki values in S(-)-enantiomer in comparison with R(+)-enantiomer.