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Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282X

Arq. Neuro-Psiquiatr. vol.71 no.7 São Paulo July 2013 


Exposure to pesticides and heterozygote genotype of GSTP1-Alw26I are associated to Parkinson's disease

Exposição a pesticidas e genótipo heterozigoto de GSTP1-Alw26I associam-se à doença de Parkinson

Gabriela S. Longo1 

Marcela S. Pinhel2 

Caroline L. Sado3 

Michele L. Gregório2 

Gisele S. Amorim2 

Greiciane S. Florim2 

Camila M. Mazeti2 

Denise P. Martins2 

Fábio N. Oliveira1 

Waldir A. Tognola1 

Marcelo A. Nakazone4 

Dorotéia R. S. Souza2 

1Medical Doctor, Department of Neuroscience, São José do Rio Preto Medical School (FAMERP), São José do Rio Preto SP, Brazil;

2Biologist Collaborator, FAMERP, São José do Rio Preto SP, Brazil;

3Medical Doctor, Federal University of São Paulo (UNIFESP), São Paulo SP, Brazil;

4Medical Doctor, Hospital de Base, São José do Rio Preto SP, Brazil.



This study aimed to analyze the frequency of GSTP1-Alw26I polymorphism and to estimate its association with toxic substances in Parkinson's disease (PD).


A study group with 154 patients - subdivided into familial and sporadic PD groups - and 158 elderly individuals without the disease (control group) were evaluated. GSTP1-Alw26I polymorphism was analyzed by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP).


Patients were significantly more exposed to pesticides compared with the control group (p=0.0004), and the heterozygote genotype associated to exposure to pesticides also prevailed in patients (p=0.0001). Wild homozygote genotype was related to tobacco use (p=0.043) and alcoholism (p=0.033) in familial PD patients.


Exposure to pesticides is associated to PD, whose effect can be enhanced when combined with the heterozygote genotype of GSTP1-Alw26I. Also, large genetic and environmental studies considering tobacco use, alcoholism, GSTP1 and PD are necessary to confirm our findings.

Key words: glutathione transferase; genetic polymorphism; Parkinson disease; xenobiotics



Analisar a frequência do polimorfismo GSTP1-Alw26I, assim como estimar sua associação com substâncias tóxicas na doença de Parkinson (DP).


A casuística avaliada foi composta por um grupo de estudo, com 154 pacientes, subdivididos em DP familial e esporádica, e outro com 158 idosos sem a doença (grupo controle). O polimorfismo GSTP1-Alw26I foi analisado por reação em cadeia da polimerase/polimorfismo de comprimento do fragmento de restrição (PCR/RFLP).


Os pacientes foram significativamente mais expostos a pesticidas, comparados com o grupo controle (p=0,0004), e o genótipo heterozigoto associado a exposição a pesticidas também prevaleceu nos pacientes (p=0,0001). O genótipo homozigoto selvagem apresentou relação com tabagismo (p=0,043) e etilismo (p=0,033) em pacientes com DP familial. Desse modo, a exposição a pesticidas está associada à DP, cujo efeito pode ser potencializado quando combinado ao genótipo heterozigoto de GSTP1-Alw26I. Estudos genético-ambientais envolvendo tabagismo, etilismo, GSTP1 e DP devem ser realizados em casuísticas numerosas, confirmando essa associação.

Palavras-Chave: glutationa transferase; polimorfismo genético; doença de Parkinson; xenobióticos

Parkinson's disease (PD) is the second most common neurodegenerative disorder, showing high prevalence in elderly patients also in Brazil, with an incidence of 150/200 cases per 100,000 inhabitants 1 . Its pathogenesis includes a complex interaction among genetic and environmental factors 2 . Sporadic cases represent 85% of PD, while 10-15% are familial and less than 5% are monogenic succession, dominant or recessive 3 . Furthermore, polymorphisms have been associated as risk factors for PD 4 , including those which determine enzymes involved in xenobiotics metabolism, such as glutathione S-transferases (GST) enzymes 5 . Based on biochemistry, immunological and structural proprieties, the GST are divided into eight classes, like π (GSTP) class, whose gene (GSTP1) is located in 11q13 human chromosome. Oxidative stress activates GST, and the P1 variant acts on the detoxification of innumerous substances capable of causing acid nucleic, lipid and protein damage 6 , especially in the brain 7 .

Individual PD risk has been associated to occupational exposure to herbicides and pesticides 8 . There is an association between GSTP1 genotypes and PD in individuals exposed to pesticides, which shows that the GSTP1 possibly affects the nigrostriatal response to neurotoxins 7,8 . Also, GSTP1 polymorphisms can influence onset age for PD 4,9 . On the other hand, there are controversies surrounding the risks or protection, involving GSTP1, tobacco use and PD 10 . GSTP1 polymorphisms have been first described by Board et al. 11 Following studies demonstrated important allelic differences in substrate selectivity, which usually reduces GSTP1 activity 7,12 . GSTP1-Alw26I distribution in population varies among different racial groups, with emphasis on Ile/Ile genotype around 45 and 65%, followed by Ile/Val from 30 to 45% and Val/Val from 5 to 10%, in Caucasian, Chinese and Korean populations 13 . Transitions of nucleotides 313 (AàG), exon 5, and 341 in exon 6 (GàT) were found, involving 2 substitutions of amino acids in the active site of the enzyme (Ile àVal and Val à Ala). The transitions altered the codon 105 of wild enzyme (GSTP1*A) from ATC (Ile) to GTC (Val) in GSTP1*B and GSTP1*C, and modified codon 114 from CGC (Ala) to GTG (Val), in GSTP1*C 7,12 . Associations can be observed between GSTP1*B and sporadic PD 14 , especially in patients older than 69 years 4 . Additionally, Shi et al. 15 indicated association of GSTP1 and PD when studying mice neuronal cells treated with neurotoxic substances. GSTP1*A prevented neuronal loss — contrary to GSTP1*B and GSTP1*C variants 15 . In this context, single nucleotide studies in neurodegenerative diseases can contribute to feature gene-environmental interactions, especially with GSTP1 and PD, since it affects cellular response to toxicity and interferes in the penetrance of hereditary PD forms and the susceptibility to idiopathic PD. This study aimed to analyze the frequency of GSTP1-Alw26I polymorphism in PD, to verify its combination with toxic substances (previous exposure to pesticides, tobacco use and alcoholism) in patients with PD and to estimate its association with the disease onset.



The studied population consisted of 312 individuals, independently of gender and with mixed racial backgrounds 16 . It was separated into two groups:

  • Study group (SG) - n=154 patients; 62.9% men and 36.1% women; average of current age: 68.2±11.6; subdivided into familial PD study group (FSG) - n=33; 69.6% men and 29.4% women; average of current age: 66.1±12, and sporadic PD study group (SSG) - n=121; 61.1% men and 37.9% women; average of current age: 68.8±11.5;

  • Control group (CG) - 158 elderly individuals without the disease or familial history of neurodegenerative diseases - 41.1% men and 57.9% women; average of current age: 69.0±8.9.

The FSG was characterized by presenting at least a first or second degree relative with PD diagnosis, and the SSG had no relatives with PD. The patients were seen in Outpatient Neurology Clinic of Hospital de Base of São José do Rio Preto Medical School (FAMERP), Brazil, in the period of 2007 through 2010. They were also subdivided into age groups, in order to provide analysis of the current age — ≤68 and >68 years 4 — and of the disease onset age, therefore defining early PD (EPD), ≤50 years, or late PD (LPD), >50 years 17 . Diagnosis of PD followed the criteria recommended by Jankovic 18 , including bradykinesia, rigidity, tremor at rest, postural instability, unilateral onset, response to L-dopa for more than five years, levodopa-induced dyskinesia, progressive disorder, persistent asymmetry and clinical course of ten years or more, as well as complementary tests 18 . The CG belonged to support groups maintained at the same institution. The participants underwent an interview, providing information concerning familial history of chronic-degenerative diseases (PD, Alzheimer's disease, among others) and living habits (previous exposure to pesticides, tobacco use and alcoholism). Exposure to pesticides consisted of any previous occupational exposure to such products, despite its duration 8 . Tobacco use included constant smoking of cigarettes, daily and continuously, for more than six months 10 . Alcoholism included the consumption of at least 40 g of alcohol per day 19 . All subjects were informed of the nature of the study and confirmed their willingness to participate by signing written consent forms. The study was approved by the Ethics Research Committee of the mentioned institution (opinion n° 151/2008 - Certificate of Appreciation Presentation Ethics — CAAE - 0029.0.140.000-08).

Genetic analysis

Analyses of the genetic polymorphism, concerning allele and genotype frequencies for GSTP1-Alw26I, were performed in the Laboratory of Molecular Biology of FAMERP. Blood samples were collected and the genomic DNA was extracted from leukocytes by standard procedures 20 . Polymerase chain reaction (PCR) was performed on an Eppendorf Mastercycler (Hamburg, Germany) with 25 µL reaction volumes containing 20 ng of genomic DNA, 1 x PCR buffer (Biosystems, Curitiba, Brazil), 2.5 mM of each primer, 200 µM of each dNTP, and 1.2 U of Taq DNA polymerase (Taq Gen). The GSTP1 gene in the DNA sequence was characterized by an A→G transition (Ile105àVal105) at nucleotide 313 (mutation site in exon 5, codon 105), using primers, as previously described 21 . Amplification was performed according to the following protocol: an initial denaturation at 94°C for 5 minutes followed by 40 cycles of 1 minute at 94°C and 3 minutes at 62°C, extension of 90 seconds at 72°C and a final cycle at 72°C for 7 minutes. The PCR product was submitted to the Alw26I restriction enzyme (Gibco) (5 U per reaction tube) in double boiler at 37°C, for 16 hours, and separated on 6% polyacrilamide gel for 50 minutes at 180 V. Fragments of 176pb, 91pb and 85pb were identified, and compared with standard Ladder (Invitrogen). One 176pb fragment characterized wild homozygote genotype (I/I), while 176pb, 91pb and 85pb fragments demonstrated heterozygote genotype (I/V); 91pb plus 85pb fragments reveled homozygose V/V (Figure). The DNA fragments were colored by GelRed Nucleic Acid Stain® and visualized by UV illumination.

Figure.  GSTP1-Alw 26I electrophoresis. 

Statistical analysis

The categorical variables including the allele and genotype frequencies for the GSTP1 polymorphism were analyzed by means of the Fisher's exact test and the χ 2 test. Statistical analysis also included Hardy-Weinberg equilibrium, t-test and binary logistic regression. A level of significance was set at a p-value of 0.05 or less.


The alleles distribution was similar between SG (isoleucine (I)=0.68; valine (V)=0.31), SSG (I=0.66; V=0.33), and CG (I=0.64; V=0.35; p>0.05; Table 1). However, the allele I was significantly higher in familial group (FSG=0.78), compared with CG (0.64; p=0.036). Wild homozygote (I/I) prevailed in FSG (63.6%) compared with SSG (38.0%; p=0.013). I/V genotype predominated in SG, SSG and CG (50.6, 56.1, and 62.0%, respectively; p>0.05); and V/V, in a reduced frequency, showed similar distribution among groups (p>0.05). FSG exhibited the pattern predicted by Hardy-Weinberg equilibrium (χ 2 =0.29; p=0.90), different from SG (χ 2 =5.01; p= 0.025), SSG (χ 2 =7.82; p=0.005) and CG (χ 2 =19.9; p<0.0001).

Table 1. Genotypic and allelic frequencies for GSTP1-Alw26I in patients with Parkinson's disease, grouped in study group, familial or sporadic, and individuals without the disease, or controls. 

GSTP1-Alw26I FSG (a)*n=33 SSG (b)*n=121 SG (c)*n=154 CG (d)*n=158
Genotype n % n % n % n %
I/I 21 63.6 46 38.0 67 43.5 53 33.5
I/V 10 30.3 68 56.1 78 50.6 98 62.0
V/V 2 6.0 7 5.7 9 5.8 7 4.4
Total 33 100 121 100 154 100 158 100
Allele n AF n AF n AF n AF
I 52 0.78 160 0.66 212 0.68 204 0.64
V 14 0.21 82 0.33 96 0.31 112 0.35
Total 66 1.00 242 1.00 308 1.00 316 1.00

FSG: familial Parkinson's disease study group; SSG: sporadic Parkinson's disease study group; SG: study group; CG: control group; axd: FSGxCG; bxc: SSGxSG; bxd: SSGxCG; cxd: SGxCG; AF: absolute frequency; p-value: I/I - axd=0.002; axb=0.013; bxd= 0.517; cxd=0.090; I/V - axd=0.001; axb=0.014; bxd=0.390; cxd=0.055; V/V - axd=0.655; axb=1.000; bxd=0.812; cxd=0.757; I/V - axd=0.036; axb=0.068; bxd=0.769; cxd=0.294. χ 2 : or Fisher's tests, p<0.05 significance.

Table 2 shows socio-demographic data such as age, sex and lifestyle (tobacco use, alcoholism and previous contact with pesticides). Age was similar among groups (p>0.05), whereas male prevailed in SG (62.9%), FSG (69.6%) and SSG (61.1%), compared with CG (41.1%; p=0.002; p=0.005; p=0.001, respectively). Tobacco use and alcoholism had low frequency and were similar among the groups (p>0.05). On the other hand, patients were more exposed to pesticides (50%) than controls (25%; p=0.0004), as well as SSG (53.0%) compared with CG (25%; p=0.0001), meanwhile FSG (38.7%) showed no significant difference from CG (25%; p=0.226).

Table 2. Social - demographic data in patients with Parkinson's disease, grouped in study group, familial or sporadic, and individuals without the disease, or controls. 

SG (a)*n=154 FSG (b)*n=33 SSG (c)*n=121 CG (d)*n=158
n % n % n % n %
Age (years)
Median 68.2 66.1 68.8 69.0
Standart deviation 11.6 12.0 11.5 8.9
Male 97 62.9 23 69.6 74 61.1 65 41.1
Female 57 37.0 10 30.3 47 38.8 93 58.8
Yes 55 38.1 8 25.8 47 41.5 50 37.0
No 89 61.8 23 74.1 66 58.4 85 62.9
Total 144 100 31 100 113 100 135 100
Yes 46 31.9 11 35.4 35 30.9 37 27.4
No 98 68.0 20 64.5 78 69.0 98 72.5
Total 144 100 31 100 113 100 135 100
Previous contact with pesticides
Yes 72 50 12 38.7 60 53.0 21 25.0
No 72 50 19 61.3 53 47.0 63 75.0
Total 144 100 31 100 13 100 84 100

FSG: familial Parkinson's disease study group; SSG: sporadic Parkinson's disease study group; SG: study group; CG: control group; axd: SGxCG; bxc: FSGxSSG; bxd: FSGxCG; cxd: SSGxCG; p-value: Age - axd=0.479; bxc=0.54; bxd=0.196; cxd=0.830; Sex - axd=0.0002; bxc=0.485; bxd=0.005; cxd=0.001; Smoking - axd=0.939; bxc=0.163; bxd=0.330; cxd=0.547; Alcoholism - axd=0.485; bxc=0.795; bxd=0.499; cxd=0.634; Pesticides - axd=0.0004; bxc=0.223; bxd=0.226; cxd=0.0001. χ 2 : or Fisher's tests, p<0.05 significance.

Tables 3 to 5 present the groups distribution according to genetic variants and environmental factors. SG, SSG and CG were similar concerning tobacco use (Table 3) and alcoholism (Table 4). However, in FSG and smoker patients there was a 75% prevalence of wild homozygote genotype (I/I), compared with GC (32%; p=0.043). I/I genotype also prevailed in FSG and alcoholic patients (FSG=72.7%; CG=27.4%; p=0.033). Heterozygote genotype (I/V) combined with pesticides prevailed in SG (60.5%=43 exposed patients/71 heterozygote patients, versus CG=24.0%=13 exposed individuals/54 heterozygote individuals; p= 0.0001). Likewise, I/V presented higher frequency combined with exposure to pesticides in SSG (59.6%=37 exposed patients/62 heterozygote patients); and FSG (60%=6 exposed patients/10 heterozygote patients), compared with GC (24.0%=13 exposed individuals/54 heterozygote individuals; p=0.0002 and p=0.053, respectively).

Table 3. Distribution of Parkinson's disease patients, grouped in study group, familial or sporadic, and individuals without the disease, smokers and no smokers, according to their genotypes for GSTP1-Alw26I. 

Genotype SG (a) FSG (b) SSG (c) CG (d) p-value
T nT T nT T GEE nT T nT
n % n % n % n % n % n % n % n % axd bxd cxd bxc
I/I 24 43.6 40 7.8 6 75 13 56.5 18 38.9 26 39.3 16 32.0 26 30.5 0.950 0.839 0.963 0.676
I/V 29 52.7 42 47.1 2 25 8 34.7 27 57.4 35 53.0 34 68.0 53 62.3 0.950 0.313 0.705 0.297
V/V 2 3.6 7 44.9 0 0 2 8.6 2 4.2 5 7.5 0 0 6 7.0 0.485 0.461 1.000
Total 55 100 89 100 8 100 23 100 47 100 66 100 50 100 85 100

FSG: familial Parkinson's disease study group; SSG: sporadic Parkinson's disease study group; SG: study group; CG: control group; T: smokers; nT: no smokers; Smokers intra-group analysis (II x -/V) - axd: SGxCG=0.305; bxd: FSGxCG=0.043; cxd: SSGxCG=0.662; bxc: FSGxSSG=0.067. p-value (χ 2 or Fisher): significance for p<0.05.

Table 4. Distribution of Parkinson's disease patients, grouped in study group, familial or sporadic, and individuals without the disease, alcoholics and no alcoholics, according to their genotypes for GSTP1-Alw26I. 

Genotype SG (a) FSG (b) SSG (c) CG (d) p-value
A nA A nA A nA A nA
n % n % n % n % n % n % n % n % axd bxd cxd bxc
I/I 22 47.8 42 42.8 8 72.7 11 55 14 40 30 38.4 12 32.4 30 30.6 0.679 0.454 0.926 0.618
I/V 20 43.4 51 52.4 2 18.1 8 40 18 51.4 44 54.4 25 67.5 62 63.2 0.937 0.721 0.968 0.715
V/V 4 8.6 5 5.1 1 9.0 1 5 3 8.5 4 5.1 0 0 6 6.1 0.103 0.250 0.192 1.000
Total 46 100 98 100 11 100 20 100 35 100 78 100 37 100 98 100

FSG: familial Parkinson's disease study group; SSG: sporadic Parkinson's disease study group; SG: study group; CG: control group; A: alcoholics; nA: no alcoholics; Alcoholics intra-group analysis (II x -/V) - axd: SGxCG=0.232; bxd: FSGxCG=0.033; cxd: SSGxCG=0.672; bxc: FSGxSSG=0.082. p-value (χ 2 or Fisher): significance for p<0.05.

Table 5. Distribution of Parkinson's disease patients, grouped in study group, familial or sporadic, and individuals without the disease, with or without previous contact with pesticides, according to their genotypes for GSTP1-Alw26I

Genotype SG (a) FSG (b) SSG (c) CG (d) p-value
P nP P nP P nP P nP
n % n % n % n % n % n % n % n % axd bxd cxd bxc
I/I 23 31.9 41 56.9 5 41.6 14 73.6 18 30.0 26 49.0 7 33.3 18 28.5 0.643 0.901 0.416 0.393
I/V 43 59.7 28 38.8 6 50 4 21.0 37 61.6 25 47.1 13 61.9 41 65.0 0.0001 0.053 0.0002 1.000
V/V 6 8.3 3 4.1 1 8.3 1 5.2 5 8.3 2 3.77 1 4.7 4 6.3 0.265 1.000 0.242 1.000
Total 72 100 72 100 12 100 19 100 60 100 53 100 21 100 63 100

FSG: familial Parkinson's disease study group; SSG: sporadic Parkinson's disease study group; SG: study group; CG: control group; P: with previous contact with pesticides; nP: without previous contact with pesticides. Pesticides intra-group analysis (II x -/V) - axd: SGxCG=0.904; bxd: FSGxCG=0.918; cxd: SSGxCG=0.991; bxc: FSGxSSG=0.503. χ 2 or Fisher's exact test: significance for p<0.05.

Earlier PD or late PD patients presented similar distribution for GSTP1-Alw26I genotype (p>0.05), also when combined with tobacco use and alcoholism (p>0.05). On the other hand, heterozygote genotype (I/V) prevailed in patients with earlier PD and previous exposure to pesticides (90%), compared with late PD, also exposed (63.9%), with no significant difference between groups, though (p=0.092). Results were also similar considering genotype distribution between ≤68 and >68 years patients (p>0.05).

The logistic regression analysis for sex, age, tobacco use, alcoholism, exposure to pesticides and GSTP1-Alw26I genotypes (Logit Y= -0.397997 +1.031093 sex +1.808364 age -0.562085 smoking -0.130537 alcoholism +1.109846 pesticide -0.654763 genotype) pointed male sex (p=0.0034), age >68 years (p<0.0001) and exposure to pesticides (p=0.001) as risk factors for PD.


In this study, with mixed ethnic Brazilian casuistics, the GSTP1-Alw26I polymorphism genotypic distribution is similar to that in the general population, considering distinct racial groups 8,13,14 . Heterozygote genotype (I/V) prevailed among familial or sporadic PD patients, and also in the control group. This distribution, although supported by some authors 8 , is different from other studies 4,14,22 . The V/V homozygote did not show any association with PD, which was also reported by other authors 8,14 . The presence of the Val105 (V) allelic variant of GSTP1 is associated with the decrease of the enzyme activity, which would favor dopaminergic neurons degeneration in PD 4,15 . However, in this study, the wild genotype (I/I) presented association with familial PD. Studies involving GSTP1 polymorphisms and familial PD are scarce 9 , making population comparisons difficult.

In this study, the familial PD group exhibited the pattern predicted by Hardy-Weinberg equilibrium, different from the pattern of other groups studied, which is also observed in other case-control studies of different genetic polymorphisms 23,24 . The selection criteria adopted in this study was to form groups of older individuals, since PD mainly affects elderly patients. Furthermore, the disease is associated with occupational exposure to pesticides, which is more common in males. This was confirmed by the logistic regression analysis that demonstrated male sex, age >68 years and exposition to pesticides as risk factors for PD. Therefore, the profiles of patient and control groups do not represent the general population concerning sex and age, influencing the distribution of genotypes. FSG also included younger patients, suggesting better representation of the general population. Additionally, absence of Hardy-Weinberg equilibrium would be expected for a wide group of genetic diseases, considering the gene contribution — although modest — for complex diseases. However, given the numerous candidate gene studies in different cases, genetic markers showing disequilibrium are scarce, which allows investigators to ignore the distribution of genotypes suggesting disequilibrium, therefore ignoring valuable information to identify casual polymorphisms 23 .

The polymorphism GSTP1-Alw26I, when related to tobacco use and alcoholism, was the same in the SG, SSG and CG groups, as well as in other studies involving smoking and PD 10,22,25 . On the other hand, there are references of tobacco protection in PD, including haplotypes of GSTP1 10 . The catalytic efficiency of the GSTP1 variants differs from that of the wild type, and it varies according to the characteristics of the substrates, manly distinct 26 . This explains the protective effect of the mutant allele regarding diol epoxides found in tobacco products 10 , in contrast with its reduced effects upon detoxification of pesticides 7 . In this study, there was an association between smoking and wild homozygote genotype in familial PD patients, confirming the studies by Pal et al. 26 and De Palma et al. 10 .

Likewise, association between I/I genotype and alcoholism was found in familial PD patients. Admittedly, alcohol abuse damages brain structures and their functions, which leads to neurodegeneration 27 . The effects of alcohol in the brain are not uniform, affecting mainly the pre- frontal cortex, the hippocampus, the cerebellum, the substantia nigra and the glia 27 . Dopaminergic neurons in the substantia nigra are believed to be damaged by alcohol during intrauterine development 27,28 . The effect of alcohol in this region is still unclear concerning brains are already developed 28 . Studies involving GSTs, alcohol, substantia nigra and PD are rare. On the other hand, GST activity is known to be reduced in hepatocytes due to alcohol exposure 29 . Retinoid X receptor α-deficient (RXRα KO) mice, which are more susceptible to ethanol-induced hepatotoxicity, showed a 56% decrease in GSTP1 activity, which demonstrates its role in the detoxification of alcohol in the liver 29 . Therefore, GSTP1 polymorphisms seem to intensify the damage caused by ethanol in hepatocytes, leading to alcoholic cirrhosis and pancreatitis 19 . The present study revealed the combination of the wild genotype (I/I) with alcoholism in familial PD patients. The small casuistic of familial patients analyzed in this study speaks in favor of detailed studies involving familial PD patients, GSTP1 polymorphisms and lifestyle.

PD patients group showed more exposure to pesticides, especially concerning the combination of such exposure and the heterozygote genotype (I/V). The GST enzymes, mainly GSTP1 4,7 , are involved in metabolizing pesticides 8 . Studies demonstrated that some kinds of pesticides, like rotenone, can cause PD-like symptoms 30 , acting as inhibitors of mitochondrial I complex. In this case, there is some evidence that dopaminergic neurons are particularly vulnerable to mitochondrial dysfunction 30 . The toxin is captured by dopamine and noradrenalin transporters and is accumulated in the cytosol, causing cellular death induced by oxidative stress and deficiency of the breathing mitochondrial chain 30 . Shi et al. 15 demonstrated protection of the neuronal dopaminergic cells of mice exposed to rotenone by the expression of the wild GSTP1 (I allele), and reduced protection by its variants expression (V allele). These data were confirmed in the present study, by means of the association of GSTP1-Alw26I heterozygote, exposure to pesticides and PD.

The V allele have been associated to late onset PD, given its prevalence in patients with more than 68 years of age 4,15 , despite the lack of association between GSTP1 polymorphisms and PD onset age in North American casuistics 14 . In this study, there was no association of GSTP1-Alw26I genotypes, current age and PD onset age. However, considering onset age, previous exposure to pesticides and the presence of the mutant allele of GSTP1-Alw26I, the group with earlier PD (PD onset before than 50 years) was significant, if compared with those with late PD onset age, which requires confirmation in wide casuistics.

The regulation of the apoptotic kinase c-jun terminal (JNK) by protein-protein direct binding and the detoxification of electrophilic compounds by conjugation with reduced glutathione have been the mainly reported GSTP1 functions 15 . The former mechanism could be associated to late onset PD in GSTP1 heterozygote patients. The GSTP1 enzyme would play an important role in the thermal shock protein system — also responsible for regulating JNK apoptosis 4 failed to act due to aging. Shi et al. 15 demonstrated that in the brains of mice treated with rotenone there was no activation of the JNK pathway of apoptosis. High level of oxidative stress was detected though, and GSTP1 detoxification with reduced glutathione was essential for neuron protection in this case 15 . That would explain the possible relation suggested in this study, between heterozygote genotype for GSTP1 in patients with previous exposure to pesticides, and the earlier PD, to be confirmed in further studies.

In conclusion, this study confirms the association among PD, male sex, ageing and exposure to pesticides, whose effects can be enhanced in combination with I/V genotype of GSTP1-Alw26I, reinforcing the relation between genetic polymorphisms involved in xenobiotics metabolism and environmental factors in PD. This is confirmed by the prevalence of the I/I genotype and tobacco or alcohol use only in the FSG, suggesting that different effects of GSTP1-Alw26I variants, due to lifestyle, determine specific subgroups of patients, which may be confirmed in other casuistics.


The authors would like to thank Moacir Fernandes de Godoy for assistance with the statistical analysis.


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Received: July 11, 2012; Received: February 28, 2013; Received: March 7, 2013

Correspondence: Gabriela S. Longo; São José do Rio Preto Medical School; Avenida Brigadeiro Faria Lima 5.416; 15090-000 São José do Rio Preto SP - Brazil; E-mail:

Support: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) - Process n° 2009/17222-0; 2008/53950-8) and São José do Rio Preto Medical School (FAMERP).

Conflict of interest: There is no conflict of interest to declare.

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