title: Enantioselective N-acetylation of N-desisopropylpropranolol by rat liver acetyltransferase.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.forename: Y
authors.initials: Y
authors.lastname: Ono
authors.forename: A
authors.initials: A
authors.lastname: Noda
authors.forename: H
authors.initials: H
authors.lastname: Noda
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000107:Acetylation; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D011433:Propranolol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; C012878:N-desisopropylpropranolol; D011433:Propranolol; D000123:Acetyltransferases; D010129:4-Aminobenzoic Acid