DETOXIFICATION GENE POLYMORPHISMS AND SUSCEPTIBILITY TO SPORADIC MOTOR NEURON DISEASE IN THE RUSSIAN POPULATION
Shadrina MI1,*, Slominsky PA1, Zherebtsova AL1, Levitsky GN2, Levitskaya NI2, Alekhin AV2, Semenova EV1, Serdyuk AV2, Skvortsova VL2, Limborska SA1
*Corresponding Author: Dr. Maria I. Shadrina - Institute of Molecular Genetics, Russian Academy of Scences, Kurchatov sq.2, Moscow 123 182, Russia; Tel.: +7-095-196-0210; Fax: +7-095-196-0221; E-mail: shadrina@ img.ras.ru
page: 31

DISCUSSION

A significant etiological factor of MND is oxygen free radicals [3]. This suggests that detoxification processes may be involved in MND pathogenesis. The genes for xenobiotic-metabolizing enzymes are highly polymorphic, so the pres­ence of deletions or slow activity alleles can unbalance the detoxification processes. CYP, GSTs, and NAT2 play major roles in many diseases and in xenobiotic metabolism. This study was undertaken to assess the possible effects on MND pathogenesis of functionally significant polymorphisms of genes involved in detoxification processes.

      It has been established that CYP2E1 and CYP2D6 may be involved in the pathogenesis of neurological diseases [9-11]. In the present study, the frequency of the CYP2E1*1D allele was considerably increased in MND patients (14% versus 2.5% in controls; p <0.001). Earlier, Bachus et al.[41] had not found any association between the CYP2E1 gene and MND. We found a considerably increased frequency of CYP2E1*1D homozygotes and the combined CYP2E1 genotype (hetero- zygote CYP2E1*1D and homozygote CYP2E1*1D) among our Russian patients. This suggests that the CYP2E1*1D polymorphism are associated with sporadic MND and that the CYP2E1*1D allele is involved in the pathogenesis of sporadic MND in patients from Russia. CYP2E1 is a producer of reac­tive oxygen species and has the unique ability to induce the iron-catalyzed Fenton reaction and to increase the hydroxyl-radical-mediated metabolism of various xenobiotics, espe­cially ethanol [42]. Itís induction in astrocytes causes oxida­tive stress, leading to the increased production of lipid peroxidation metabolites and decreased concentrations of glutathione [43], which may be involved in the degeneration of motor neurons. We also found that presence of the CYP2E1*1D allele is significantly correlated with more malignant forms of MND, such as truncal onset and diffuse onset ALS and progressive bulbar palsy. The same MND mutation may result in highly variable phenotypes within one family [44]. The products of modifier genes or susceptibility factors can be responsible for part of this phenotypic varia­bility. These phenomena probably explain the correlation between the CYP2E1*1D genotype and the clinical features reported here.

      A deficiency in the CYP2D6 enzyme is inherited as an autosomal recessive trait and result in poor metabolizers [13]. The CYP2D6*4 allele is associated with a deficiency of the CYP2D6 enzyme [16]. This abnormal gene product may have some novel effect that leads directly to, or promotes, the degeneration of motor neurons. We found CYP2D6*4 homozygote to be more frequent among our patients than among our controls, but not significantly so. A considerably increased frequency of the CYP2D6*4 allele in ALS patients has been reported [10]. This suggests that the CYP2D6*4 allele may be a very weak risk factor for development of MND in our population.

      The GST protect against oxidative stress by removing toxic compounds and reactive oxygen species via conjugation with glutathione. Deletion variants of the GSTT1 and GSTM1 genes and the GSTP1 gene Ile105Val polymorphism in exon 5 correlate with increased susceptibility to various diseases, including chronic bronchitis, arteriosclerosis, cancer and neu­rological diseases [22,23]. Because environmental toxins and oxidative stress have been implicated in neurological dysfunc­tion, the lack of protection afforded by the null variants of the GSTT1 and GSTM1 isoforms and the valine-containing GSTP1 isoforms may be expected to be associated with MND. The Ile105Val polymorphism showed no difference in the GSTP1 genotype distributions between control and patient groups. However, we found that the wild type allele genotype is associated with classical upper and lower MN involvement, whereas the valine allele is significantly correlated with pre­dominant lower and predominant upper MN involvement. Patients with the 105Val allele have less malignant variations of motor neuron involvement. Thus, the GSTP1 gene may act as a modifier gene and be responsible for part of the MND phenotypic variability in our population.

      We found the GSTM1(0/0) frequency to be significantly decreased and the GSTM1(+) frequency to be significantly increased among our patients. Apart from the deletion allele, there are two common alleles, GSTM1*A and GSTM1*B, which involve base pair exchanges. It has been suggested that homo- and heterozygotes for GSTM1*A and GSTM1*B are less susceptible to different diseases than are carriers of the GSTM1(0/0) genotype, and that the heterozygous AB geno­type may protect against MND as this combination protects against colorectal and brain cancer [45]. The PCR method we used does not distinguish the GSTM1*A and GSTM1*B alleles. The use of another method and greater numbers of patients may resolve this point. We conclude that three genes of phases I and II of the detoxification system, i.e., CYP2E1, GSTP1 and GSTM1, participate in the development of spo­radic MND in Russia.

 




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