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)

Drug metabolizing enzymes are of paramount importance in drug detoxification as well as chemical mutagenesis, carcinogenesis and toxicity via metabolic activation. Thus genetically determined differences in the activity of these enzymes can influence individual susceptibility to adverse drug reactions, drug induced diseases and certain types of chemically induced cancers. The genetic polymorphisms of three human drug metabolizing enzymes, namely N-acetyltransferase and two cytochrome P-450 isozymes (P-4502D6: debrisoquine/sparteine polymorphism, P-4502C8-10: mephenytoin polymorphism) have been firmly established. Based on the metabolic handling of certain probe drugs, the population can be divided into two phenotypes: the rapid acetylator/extensive metabolizer and slow acetylator/poor metabolizer. These polymorphisms have provided useful tools to study the relationship between genetically determined differences in the activity of drug metabolizing enzymes and the risk for adverse drug reactions and certain types of chemically-induced diseases and cancers. With regard to the susceptibility of the two phenotypes, drug mediated toxicity for the following scenarios can be anticipated. (1) The toxicity of the drug is caused by the parent compound and the elimination of the drug proceeds exclusively via the polymorphic enzyme. No alternate pathways of biotransformation are available. Thus the slow acetylator/poor metabolizer phenotype will be more prone to such a type of toxicity since, at the same level of exposure, this phenotype will accumulate the drug as a result of impaired metabolism (e.g. isoniazid polyneuropathy, perhexiline polyneuropathy, pesticide induced Parkinsons disease). (2) The polymorphic pathway is a major route of detoxification. Impairment of this pathway shifts the metabolism to an alternate pathway via which a reactive intermediate is being formed. In such a situation the slow acetylator/poor metabolizer phenotype constitutes a major risk factor for toxicity (e.g. isoniazid hepatotoxicity). (3) The toxicity is mediated by a reactive intermediate generated by a polymorphic enzyme. Hence extensive metabolizers are at a much higher risk than poor metabolizers to develop toxicity or cancer (e.g. bronchial carcinoma in smokers, not chemically induced aggressive bladder cancer).
 ...
PMID:Genetically determined differences in drug metabolism as a risk factor in drug toxicity. 147 Nov 65

Certain anticonvulsant drugs require N-acetylation as a major route of metabolic clearance. Single point mutations of the polymorphic N-acetyltransferase gene (pNAT) are the primary cause for impaired drug acetylation. Pharmacokinetic parameters are altered in slow acetylator phenotypes and this may compromise drug safety. Genetic analysis of allelic frequencies of individual pNAT genotypes point to significant increases in carriers of the S1/wt and S3/wt (P < 0.05) allele and a significant reduction in carriers of the S2/S2 (P < 0.01) allele, when control and epileptic patients are compared. Furthermore, the presumed link between the cytochrome P450 CYP2D6 polymorphism and the pathogenesis of Parkinson's disease led us to investigate, whether a similar relationship can be expected for other CNS disorders. Our findings indicate that poor metabolizers are more frequent (P < 0.05) amongst epileptic patients, when compared with a control population. An estimate of the odds ratio may suggest an increased risk [95% CI (confidence interval) 1.043-4.734] of up to 5-fold in epileptic patients carrying this mutation. This provides further evidence for a potential link between the debrisoquine hydroxylase gene polymorphism and CNS disorder and therefore warrants further study.
 ...
PMID:pNAT and CYP2D6 gene polymorphism in epileptic patients. 798 Jun 40

A very early event in the pathogenesis of idiopathic Parkinson's disease (PD) has been proposed to be an elevated translocation of L-cysteine (CySH) and/or glutathione (GSH) into pigmented dopaminergic cell bodies in the substantia nigra (SN) in which cytoplasmic dopamine (DA) is normally autoxidized to DA-o-quinone as the first step in a reaction leading to black neuromelanin polymer. Such an elevated influx of CySH and GSH would be expected to initially result in formation of 5-S-cysteinyldopamine (5-S-CyS-DA) and 5-S-glutathionyldopamine (5-S-Glu-DA), respectively, and might account for the massive irreversible loss of GSH and progressive depigmentation of SN cells that occurs in the Parkinsonian brain. However, 5-S-Glu-DA has not been detected in the Parkinsonian brain. Furthermore, although the 5-S-CyS-DA/DA and 5-S-CyS-DA/homovanillic acid concentration ratios increase significantly in the SN and cerebrospinal fluid, respectively, of PD patients, the absolute concentrations of 5-S-CyS-DA are extremely low and similar to those measured in age-matched control patients. One explanation for these observations is that 5-S-CyS-DA might be intraneuronally oxidized to more complex cysteinyldopamines and a number of dihydrobenzothiazines (DHBTs) and benzothiazines (BTs). Similarly, 5-S-Glu-DA might be intraneuronally oxidized to more complex glutathionyldopamines. In this investigation, however, it is demonstrated that 5-S-Glu-DA is rapidly metabolized in rat brain to 5-S-CyS-DA and 5-S-(N-acetylcysteinyl) dopamine (5) in reactions mediated by gamma-glutamyl transpeptidase (gamma-GT) and cysteine conjugate N-acetyltransferase. Similarly, 5-S-CyS-DA is metabolized to 5 in rat brain although more slowly than 5-S-Glu-DA. These reactions occur most rapidly in the midbrain, a region that contains the SN. Furthermore, 5, 2-S-(N-acetylcysteinyl)dopamine (6) and 2,5-di-S-(N-acetylcysteinyl)-dopamine (9) are toxic when administered into mouse brain having LD50 values of 14, 25, and 42 micrograms, respectively, and evoke a profound hyperactivity syndrome. These results suggest that the failure to detect 5-S-Glu-DA and the presence of only very low levels of 5-S-CyS-DA in Parkinsonian SN tissue and CSF might be related to both their intraneuronal oxidation and extraneuronal metabolism to N-acetylcysteinyl conjugates of DA. Furthermore, the toxic properties and neurobehavioral responses evoked by 5, 6, and 9 raise the possibility that these N-acetylcysteinyl conjugates of DA, in addition to certain cysteinyldopamines, DHBTs and BTs, might include endotoxins that contribute to SN cell death and other neuronal damage that occurs in PD. Methods are described for the synthesis of several N-acetylcysteinyl conjugates of DA, and their redox behaviors have been studied using cyclic voltammetry.
 ...
PMID:Synthesis, redox properties, in vivo formation, and neurobehavioral effects of N-acetylcysteinyl conjugates of dopamine: possible metabolites of relevance to Parkinson's disease. 890 66

The N-acetyltransferase-2 gene (NAT-2) has been associated with Parkinson's disease. The genotype associated with slow acetylation has been reported to be increased in patients with Parkinson's disease. Three mutant alleles M1, M2, and M3 of NAT-2 were investigated in 80 patients with idiopathic Parkinson's disease and 161 age matched randomly selected controls from a prospective population based cohort study. The allelic frequencies and genotypic distributions in patients were very similar to those found in controls. In controls the frequency of the wild type allele increased significantly with age suggesting that the mutant alleles are associated with an increased risk of mortality. These findings suggest that NAT-2 polymorphism is not a major genetic determinant of idiopathic Parkinson's disease, but may be a determinant of mortality in the general population.
 ...
PMID:N-acetyltransferase-2 polymorphism in Parkinson's disease: the Rotterdam study. 1048 1

Polymorphic N-acetyltransferase (NAT2) is involved in the metabolism of several compounds relevant in pharmacology or toxicology, with diverse clinical consequences. Inter-ethnic variations in distribution of the acetylation phenotype are significant. The caffeine test is most often used to assess the acetylation phenotype and to identify rapid and slow acetylators. The NAT2 phenotype could account for the increased risk of certain side effects in slow acetylators treated with isoniazid (particularly peripheral neuropathies and lupus erythematosus), although therapeutic efficacy seems to be independent of the acetylation status. Hypersensibility reactions with sulfonamides (including Lyell and Stevens-Johnson syndromes) are more frequent in slow acetylators, who also show poor tolerance to sulfasalazine and dapsone. In contrast, myelotoxicity induced by amonafide is more frequent in rapid acetylators, probably because of increased production of a toxic metabolite of the drug. In carcinogenesis, NAT2 may play a protective role against bladder cancer, although studies have shown contradictory results. Slow acetylators may have a risk of developing primitive liver cancer. For lung cancer, data are not conclusive, but slow acetylation status may predispose to mesothelioma in subjects exposed to asbestos. No relation has been found between acetylation phenotype and breast cancer. Contradictory results were reported on its role in colorectal cancer. Non-smoking type 1 diabetics may be at increased risk of nephropathy if they are rapid acetylators. Parkinson's disease may be more frequent among slow acetylators, but again, data have shown contradictory results. Finally, a poor acetylator phenotype may predispose to atopic diseases.
 ...
PMID:[Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism]. 1261 Nov 96