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
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
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DOI：
10.1016/0006-2952(93)90222-i
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发表时间：
1993-06-22
影响因子：
5.8
通讯作者：
STEULET, AF
中科院分区：
文献类型：
--
作者：
WALDMEIER, PC;BUCHLE, AM;STEULET, AF
本文研究了口服活性铁螯合剂1，2-二甲基-3-羟基吡啶-4-酮（L_1，CP_（20））对大鼠多巴胺（DA）和5-羟色胺（5-HT）代谢的影响。在100 mg/kg腹腔注射时，它降低大鼠纹状体中DA、5-HT、5-羟基吲哚乙酸和特别是高香草酸的水平达数小时。这些效应是由儿茶酚-O-甲基转移酶（COMT; EC 2.1.1.6）、酪氨酸[酪氨酸，四氢蝶啶：氧氧化还原酶（3-羟基化）（EC 1.14.16.2）]和色氨酸羟化酶[色氨酸，四氢蝶啶：氧氧化还原酶（5-羟基化）（EC 1.14.16.4）]的伴随抑制引起的，具有相似的时间过程。通过外源性L-二羟基苯丙氨酸（L-DOPA）转化为其O-甲基化衍生物测定，COMT被抑制的阈值剂量为约1 mg/kg i. p.，ED 50为约10 mg/kg i. p.。在中枢脱羧酶抑制后，酪氨酸和色氨酸羟化酶活性分别通过多巴和5-羟色氨酸的积累来测量，在纹状体和皮质中受到抑制，阈值剂量为3-10 mg/kg，ED 50约为20-30 mg/kg，腹膜内或口服。虽然COMT抑制L1可能与后者药物与正常酶底物的结构相似性有关，但酪氨酸和色氨酸羟化酶抑制更可能是由于与这些酶结合的铁的配位。100 mg/kg i. p.去铁胺未显示出相当的效果。目前尚不清楚这是否与脑和/或细胞渗透性差有关，或者多齿螯合剂是否不太适合作为芳香族氨基酸羟化酶的抑制剂。
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 ED50 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 ED50S 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.