Effects of norlaudanosolinecarboxylic acids on enzymes of catecholamine metabolism

Enzymes involved in catecholamine metabolism were assayed in the presence of a new class of naturally occurring tetrahydroisoquinoline alkaloids, the norlaudanosolinecarboxylic acids (NLCAs). NLCAs inhibited tyrosine hydroxylase noncompetitively with respect to its substrate tyrosine and the cofactor, 6-methyltetrahydropterin [NLCA K(i) = 4 x 10 ^-4 M; 3',4'-deoxynorlaudanosolinecarboxylic acid (DNLCA) K(i) = 1.5 x 10 ^-4 M]. Adrenal dopamine β-hydroxylase was also inhibited by NLCAs [3'-O-methylnorlaudanosolinecarboxylic acid (MNLCA) K(i) = 1.2 x 10 ^-4 M] and NLCA is a competitive inhibitor of norepinephrine methylation by hepatic catechol-O-methyltransferase [NLCA K(i) = 5.6 x 10 ^-5 M]. While a slight reduction of rat adrenal monoamine oxidase by MNLCA was also observed, NLCA did not affect the oxidation of tyrosine by D-amino acid oxidase. Kinetic patterns of tyrosine aminotransferase and aromatic amino acid decarboxylase from rat liver were not altered by addition of 1 to 10 x 10 ^-5 M NLCA or its 3'-O-methyl ether (MNLCA). In vivo studies of brain tyrosine metabolism in mouse neonates corroborated results on the in vitro effect of DNLCA on tyrosine hydroxylase. The potential of high-pressure liquid chromatography was demonstrated in both enzyme assays and radiometric studies of in vivo metabolism.