- Genetics, drugs and environmental factors in parkinson's disease (A case-control study)
Genetics, drugs and environmental factors in parkinson's disease
A case-control study
ANTONIO LUIZ DOS SANTOS WERNECK*, HELCIO ALVARENGA
Arq. Neuro-Psiquiatr. vol.57 n.2B São Paulo June 1999. [Open Access]
ABSTRACT - A case-control study of Parkinson's disease (PD) was conducted in the city of Rio de Janeiro based on the assumption that neurotoxins with secondary parkinsonian action may be related to the development of Parkinson's disease. Ninety-two subjects with PD and 110 controls were queried through a questionnaire in order to investigate possible risk factors for the disease. The following factors were studied: herbicides/pesticides, exposure to chemicals, ingestion of drugs with secondary PD effects, rural life, water well source, family history, cranial trauma and cigarette smoking. Study of mentioned factors was achieved through univariate, stratified and multivariate analyses. Univariate and multivariate analyses demonstrated that PD was positively associated with family history (OR = 14.5; CI = 2.98 - 91.38), with the use of drugs with secondary PD action (OR = 11.01; CI = 3.41 - 39.41) and with exposure to chemical agents (OR = 5.87; CI = 1.48 - 27.23). PD was found to be inversely associated with cigarette smoking (OR = 0.39; IC = 0.16 - 0.95). Stratified analysis only confirmed family history and drug use, besides demonstrating that cigarette consumption could be a protection factor, when aforementioned factors were involved. This study might be a warning as to the cares that need to be taken regarding drug use and occupational exposure to chemical agents, as both types of substances present secondary PD action.
KEY WORDS: Parkinson's disease, genetics, chemical agents, drugs, environmental factors.
Recent studies on etiology of Parkinson's disease (PD) chiefly point to a genetic predisposition associated to a possible participation of internal and or external neurotoxins. Over the last decade, numerous studies showed the participation of external toxins in the genesis of the disease. Evidence of an inadequate performance of the cytochrome P-450 enzymatic complex in PD reinforced the idea of the occurrence of deficient metabolizing of xenobiotic substances, which led to the hypothesis that parkinsonian patients are more vulnerable to the action of some neurotoxins1. One of the studies investigated the participation of cytochrome P-450 2D6 (CYP2S6) and M1 S-transferase glutathione (GSTM1) genes, whose action is based on the programming of enzymes responsible for detoxification of external toxins. It could be observed that individuals who posses the CYP2D6L allele have 2.4 times more chances of being affected with PD than controls. Furthermore, if the individual has the M1 S-transferase (GSTM1) the possibility is increased from 11 to 14 times2. On the other hand, some diseases can be transitory — disseminated lupus erythematosus, myasthenia gravis, scleroderma, diabetes and arterial hypertension — triggered by the simple action of a drug, and it is not uncommon that such diseases only come to their full clinical development many years later. So, one might suspect that some cases of transitory parkinsonism represent a symptomatic expression of PD, which was only transitorily facilitated by the action of a specific neurotoxin. The presence of correlated risk factors in transitory parkinsonism and in PD also support this concept. This becomes clear, for example, when family history and use of chemical agents are observed in both syndromes3,4.
In 1986, Calne et al.5 proposed that diseases like Alzheimer's, Parkinson's and amyotrophic lateral sclerosis were determined by an environmental agent which was responsible for long-term progressive damage, with clinical manifestations only occurring after age-related neuronal losses. Regarding PD, Langston6 proposed that substantia nigra neurons react in the presence of a toxin, with a subsequent reduction in their number. In view of dopamine loss resulting from this action, there is an activation of the oxidative compensatory metabolism, which would be responsible for the increase of dead neurons in the substantia nigra. The finding that clinical, biochemical, and pathological features of PD are caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)7 suggests that a similar neurotoxin may trigger PD. Evidence obtained through reduction positron emission tomography of the progressive damage of dopaminergic function of patients exposed to the MPTP adds up to this hypothesis8. This fact by itself suggests the existence of damage "in-progress" of the substantia nigra neurons. Initial evidence that could lead to explain MPTP's possible action in the cell, was described by Nicklas et al.9, demonstrating that the MPP+ is a potential inhibitor to the NADQ Co Q1 reductase, or Complex I, of the mitochondrial respiratory enzymatic chain. Some years later, other studies demonstrate that there was an important reduction in the activity of the NADQ Co Q1 reductase of the substantia nigra mitochondrian neurons in parkinsonians, suggesting that this deficiency could be related to the onset of the pathological process of PD10. This same kind of deficiency of the respiratory enzymatic chain was also considered as secondary due to the action of neuroleptics and calcium antagonists11,12. Some studies are also disclosing the fact that drugs with parkinsonian action can cause neuronal injury in the substantia nigra13, and this can increase PD risk. Besides that, it has been observed that an increase of circa 18% in PD incidence occur in elderly patients who made use of neuroleptics, monitored for a minimum period of 21 months even prior to PD diagnosis14.
In view of such data, and coupled with the easy over-the-counter sale of drugs with parkinsonian secondary action in Brazil, we decided to conduct a case-control-study in the city of Rio de Janeiro. The goal was to determine the relative etiologic significance on the development of PD of factors such as: rural living, potable water well-source, central or peripheral trauma, family history, herbicides and insecticides, cigarette smoking, occupational exposure to chemical agents, and use of drugs with secondary parkinsonian action.
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