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 co ncentrations ranging from 10 to 200 mu M. The cytosol fraction of a rat liv er 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 t he presence of infinite AcCoA (250 mu M), the K-m value was calculated to b e 67.5 or 62.4 mu M, and the V-max value was 0.462 or 0.205 nmol/min/mg pro tein, Based on these findings, the enantioselective N-acetylation of NDP wa s 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 c ompetitively inhibited by the exogenous arylamine, p-aminobenzoic acid (PAB A), which is well-known to be a typical substrate of AT, The presence of en antioselective inhibition for AcNDP formation was thus confirmed based on t he K-i values, 440 mu M in the case of R(+)-NDP and 250 mu M in the case of S(-)-NDP, respectively, i.e. two-fold enantioselective inhibition was demo nstrated based on the Ki values in S(-)-enantiomer in comparison with R(+)- enantiomer.