INHIBITION OF CATECHOL-O-METHYLTRANSFERASE (COMT) AS WELL AS TYROSINEAND TRYPTOPHAN-HYDROXYLASE BY THE ORALLY-ACTIVE IRON CHELATOR, 1,2-DIMETHYL-3-HYDROXYPYRIDIN-4-ONE (L1, CP20), IN RAT-BRAIN IN-VIVO

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 interfer e 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 p articularly homovanillic acid in the rat striatum for several hours. T hese effects were shown to result from concomitant inhibition of catec hol-O-methyltransferase (COMT; EC 2.1.1.6), tyrosine [tyrosine, tetrah ydropteridine: oxygen oxidoreductase (3-hydroxylating) (EC 1.14.16.2)] and tryptophan hydroxylase [tryptophan, tetrahydropteridine: oxygen o xidoreductase (5-hydroxylating) (EC 1.14.16.4)], with similar time-cou rses. COMT was inhibited with a threshold dose of about 1 mg/kg i.p. a nd an ED50 of about 10 mg/kg i.p. as determined by the conversion of e xogenous L-dihydroxyphenylalanine (L-DOPA) to its O-methylated derivat ive. Tyrosine and tryptophan hydroxylase activities as measured by the accumulation of DOPA and 5-hydroxytryptophan, respectively, after cen tral decarboxylase inhibition, were inhibited in striatum and cortex, with threshold doses of 3-10 mg/kg and ED50S of about 20-30 mg/kg i.p. or p.o. While COMT inhibition by L1 is probably related to the struct ural similarity of the latter drug with the normal enzyme substrates, tyrosine and tryptophan hydroxylase inhibition is more likely due to c oordination 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 hydr oxylases.