Effect of l-aromatic amino acid decarboxylase inhibition on metabolism of dihydroxyphenylalanine by isolated perfused rat liver

Abstract

The isolated perfused rat liver was used to study the effect of an inhibitor of l-aromatic amino acid decarboxylase, N-( d,l-seryl)- N′-(2,3,4-trihydroxybenzyl)-hydra-zine (RO 4-4602), on hepatic metabolism of l-3,4-dihydroxyphenylalanine ( l-dopa). When inhibitor was added to the perfusate before addition of l-dopa-3- 14C, the amount of radioactivity in the liver was less. Rapid uptake of l-dopa by erythrocytes in the perfusate removed 28 per cent of it from plasma in control perfusions, and this was unaffected by RO 4-4602. However, radioactivity in erythrocytes decreased to 7 per cent of the dose during control perfusions but only to 19 per cent when RO 4-4602 had been added. In all perfusions, about half of the 14C disappeared from plasma in 5 min. In control perfusions, there was a continued decrease in 14C in plasma during the first hour, to 35 per cent of the dose, but when RO 4-4602 had been added the decrease after the first 5 min was negligible. Between 5 and 120 min after injection, the half-life of l-dopa in plasma was 27 min in control perfusions and 57 min if RO 4-4602 had been added. However, between 120 and 300 min after dopa injection, when comparatively small amounts of it were present in plasma, the disappearance was more rapid in the presence of RO 4-4602. Excreted bile contained 44 per cent of the dose in control perfusions but only 8 per cent if RO 4-4602 had been added to the perfusate. When RO 4-4602 was added, the formation of conjugates of acidic and neutral metabolites of dopamine was decreased, especially the glucuronides of N-acetyldopamine and N-acetyl-3- O-ethyldopamine, the major metabolites in bile. However, there was an almost compensatory increase in the formation of 3-methoxy-4-hydroxyphenylalanine by direct O-methylation of l-dopa. The effect of RO 4-4602 did not appear to be prolonged because it was less obvious when the inhibitor was added 30–60 min before the l-dopa.