Inhibition of catechol- O-methyltransferase (COMT) as well as tyrosine and tryptophan hydroxylase by the orally active iron chelator, 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20), in rat brain in vivo

Abstract

The orally active iron chelator, 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20) proposed for reduction of iron overload in hemoglobinopathic patients, was studied in rats with respect to its ability to interfere with dopamine (DA) and serotonin (5-HT) metabolism. At 100 mg/kg i.p., it reduced the levels of DA, 5-HT, 5-hydroxyindoleacetic acid and particularly homovanillic acid in the rat striatum for several hours. These effects were shown to result from concomitant inhibition of catechol- O-methyltransferase (COMT; EC 2.1.1.6), tyrosine [tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating) (EC 1.14.16.2)] and tryptophan hydroxylase [tryptophan, tetrahydropteridine:oxygen oxidoreductase (5-hydroxylating) (EC 1.14.16.4)], with similar time-courses. COMT was inhibited with a threshold dose of about 1 mg/kg i.p. and an ed 50 of about 10 mg/kg i.p. as determined by the conversion of exogenous l-dihydroxyphenylalanine ( l-DOPA) to its O-methylated derivative. Tyrosine and tryptophan hydroxylase activities as measured by the accumulation of DOPA and 5-hydroxytryptophan, respectively, after central decarboxylase inhibition, were inhibited in striatum and cortex, with threshold doses of 3–10 mg/kg and ed 50s of about 20–30 mg/kg i.p. or p.o. While COMT inhibition by L1 is probably related to the structural similarity of the latter drug with the normal enzyme substrates, tyrosine and tryptophan hydroxylase inhibition is more likely due to coordination to iron bound to these enzymes. Desferrioxamine at 100 mg/kg i.p. did not show comparable effects. It is not known whether this relates to poor brain and/or cell penetration, or whether multidentate chelators are less suitable as inhibitors of aromatic amino acid hydroxylases