Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic tryptophan 2,3-dioxygenase (TDO) is one of the rate-limiting enzymes in tryptophan catabolism and plays an important role in regulating the physiological flux of tryptophan into relevant metabolic pathways. In this study, we determined the effect of the non-steroidal anti-inflammatory agents, tolmetin and sulindac, on rat liver TDO activity and the subsequent changes in the hippocampal and striatal neurotransmitter levels. The amount of melatonin produced by the pineal gland was also measured using high performance liquid chromatography (HPLC). Treatment of rats with tolmetin or sulindac (5 mg/kg/bd for 5 days) significantly inhibited liver TDO activity. The results show that whilst tolmetin and sulindac increase serotonin levels in the hippocampus, these agents also significantly reduce dopamine levels in the striatum. Tolmetin, but not sulindac, increased the amount of melatonin produced by the pineal gland. The results of this study suggest that whilst tolmetin and sulindac may be beneficial for patients suffering from depression, these agents also have the potential to induce adverse effects in patients suffering with neurological disorders such as Parkinson's disease.
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PMID:Non-steroidal anti-inflammatory agents, tolmetin and sulindac, inhibit liver tryptophan 2,3-dioxygenase activity and alter brain neurotransmitter levels. 1695 80

The effects of three hydrazine derivatives on the enzymes of the tryptophan oxidative pathway and of nicotinamide nucleotide synthesis have been studied using preparations from rat liver. The compounds used were Benserazide and Carbidopa, two inhibitors of aromatic amino acid decarboxylase used together with dopa in the treatment of Parkinson's disease, and the anti-tubercular agent isoniazid. All three drugs inhibited tryptophan oxygenase and kynureninase, at concentrations that are likely to be encountered in vivo following administration to patients or experimental animals. Isoniazid, but not Benserazide or Carbidopa, also inhibited 3-hydroxy-anthranilate oxidase and nicotinamide phosphoribosyltransferase. However, these two enzymes were of the drug far in excess of those likely to be encountered in vivo. On the basis of the in vitro enzyme inhibition studies, it is not possible to explain why patients treated with isoniazid (without supplementary vitamin B(6)) develop clinical pellagra, while those treated with Benserazide or Carbidopa do not, despite biochemical evidence of niacin deficiency. It is suggested that this difference may be due either to differences in the intake of dietary niacin in these two groups of patients, or more probably to differences in the metabolism of the drugs and in their interactions with enzymes in vivo that are not apparent in vitro.
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PMID:Inhibition in vitro of the enzymes of the oxidative pathway of tryptophan metabolism and of nicotinamide nucleotide synthesis by benserazide, carbidopa and isoniazid. 2022 44