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
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.
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.