title: Side-chain metabolism of propranolol: involvement of monoamine oxidase and mitochondrial aldehyde dehydrogenase in the metabolism of N-desisopropylpropranolol to naphthoxylactic acid in rat liver.
abstract: We examined the metabolism of N-desisopropylpropranolol (NDP), which is generated from propranolol (PL) by side-chain N-desisopropylation, to naphthoxylactic acid (NLA) in rat liver. S(-)-NDP (S-NDP) and R(+)-NDP (R-NDP) were enantioselectively metabolized to NLA in isolated rat hepatocytes and in an enzyme reaction system of rat liver mitochondria with cofactor NAD+. Furthermore, the clearance profiles of NDP enantiomers were examined in an enzyme reaction system of rat liver mitochondria without NAD+. The amounts of S-NDP remaining in the incubation medium were similar to those of R-NDP, suggesting that monoamine oxidase (MAO) catalyzes the deamination of NDP to the aldehyde intermediate, but fails to deaminate enantioselectively S-NDP or R-NDP. Cyanamide, a potent inhibitor of aldehyde dehydrogenase (ALDH), markedly decreased the formation of NLA from racemic NDP in the enzyme reaction system of rat liver mitochondria with NAD+. When rat liver cytosol and microsomes were added to this enzyme reaction system, no significant alterations were observed in the amount of NLA generated from racemic NDP. We concluded that MAO deaminates NDP to an aldehyde intermediate, and that mitochondrial ALDH subsequently catalyzes the enantioselective metabolism of the aldehyde intermediate to NLA in rat liver.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kumamoto University, Japan. yorishig@gpo.kumamoto-u.ac.jp
authors.forename: Yorishige
authors.initials: Y
authors.lastname: Imamura
authors.forename: Xiuzohng
authors.initials: X
authors.lastname: Wu
authors.forename: Atsuko
authors.initials: A
authors.lastname: Noda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Noda
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D018929:Cell Culture Techniques; D002851:Chromatography, High Pressure Liquid; D003484:Cyanamide / Q000494:pharmacology; D003600:Cytosol; D000077604:Fomepizole; D022781:Hepatocytes; D007773:Lactates / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology*; D008995:Monoamine Oxidase / Q000378:metabolism*; D010084:Oxidation-Reduction; D011433:Propranolol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D000931:Antidotes; D007773:Lactates; D011720:Pyrazoles; C002685:naphthoxylactic acid; C012878:N-desisopropylpropranolol; D003484:Cyanamide; D000077604:Fomepizole; D011433:Propranolol; D000449:Aldehyde Reductase; D008995:Monoamine Oxidase