Side-chain metabolism of propranolol: involvement of monoamine oxidase andaldehyde reductase in the metabolism of N-desisopropylpropranolol to propranolol glycol in rat liver

The further metabolism of N-desisopropylpropranolol (NDP), a side-chain met abolite of propranolol (PL), was investigated in isolated rat hepatocytes. Propranolol glycol (PGL) was generated from NDP as a major metabolite. Naph tetrazole (NTE), a potent inhibitor of monoamine oxidase (MAO), significant ly retarded the disappearance of NDP from the incubation medium, suggesting the involvement of MAO in the deamination of NDP to an aldehyde intermedia te. In a reaction mixture of rat liver mitochondria and cytosol with NADPH, phenobarbital, a specific inhibitor of aldehyde reductase, and 4-nitrobenz aldehyde (4-NBA), a substrate inhibitor of aldehyde reductase, decreased th e formation of PGL from NDP. 4-NBA was a competitive inhibitor of the enzym e responsible for the PGL formation. The optimal pH for the formation of PG L from NDP in the reaction mixture was approximately 8.0. Based on these re sults, we propose the possibility that, in the rat liver, MAO catalyzes the oxidative deamination of NDP to an aldehyde intermediate and the formed al dehyde intermediate is subsequently reduced to PGL by aldehyde reductase. F urthermore, the enantioselective metabolism of NDP to PGL was examined. In isolated rat hepatocytes, the amount of PGL formed from S-NDP [S(-)-form of NDP] was larger than that of PGL formed from R-NDP [R(+)-form of NDP]. (C) 2001 Elsevier Science Inc. All rights reserved.