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)

Susceptibility to develop Parkinson's disease has been linked to abnormalities of P450 enzyme function. Multiple P450 enzymes are expressed in brain but the relationship of these to Parkinson's disease is unknown. We have investigated the expression of P450 enzymes in the rat substantia nigra and their co-localization in tyrosine hydroxylase-positive neurons and astrocytes. Immunohistochemistry was performed using anti-peptide antisera against the following P450 enzymes: CYP1A1, CYP1A2, CYP2B1/2, CYP2C12, CYP2C13/2C6, CYP2D1, CYP2D4, CYP2E1, CYP3A1, CYP3A2 and NADPH-P450 oxidoreductase. Immunoreactivity in nigral cells was found only for CYP2E1 and CYP2C13/2C6. CYP2E1 immunoreactivity was localized to many midbrain nuclei including the substantia nigra pars compacta but not the substantia nigra pars reticulata while immunoreactivity to CYP2C13/2C6 was found in the substantia nigra pars compacta, substantia nigra pars reticulata and many other midbrain nuclei. Sections of rat midbrain double labelled for either CYP2E1 or CYP2C13/2C6 and tyrosine hydroxylase or glial fibrillary acidic protein were examined for co-localization by confocal laser scanning microscopy. CYP2E1 and CYP2C13/2C6 immunoreactivity was found in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta but not in glial cells. CYP2C13/2C6, but not CYP2E1, was also found in non-glial, non-tyrosine hydroxylase-expressing cells in the substantia nigra pars reticulata. Isoniazid induction increased CYP2E1 fluorescence signal intensity from nigral dopaminergic neurons. At least two P450 enzymes are found in nigral dopamine containing cells and one, namely CYP2E1, is selectively localized to this cell population. CYP2E1 is a potent generator of free radicals which may contribute to nigral pathology in Parkinson's disease. The expression of CYP2E1 in dopaminergic neurons in substantia nigra raises the possibility of a causal association with Parkinson's disease.
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PMID:Co-localization of P450 enzymes in the rat substantia nigra with tyrosine hydroxylase. 988 65

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