Motor neuron disease (MND) is a late-onset neurode­generative disorder characterized by progressive degeneration of motor cells of the brain and spinal cord [1]. Epidemiological studies indicate a 5-10% incidence of familial MND. The clinical and pathological features of familial and sporadic MND are virtually identical.

      Motor neuron disease is a multifactorial disease that involves complex interactions between genes and environ­mental factors [2]. Despite years of research, the genetic basis of MND remains to be fully elucidated. A significant etio­logical factor may be oxygen free radicals which, at high concentrations, damage neuronal cells [3]. Superoxide dismu­tase (SOD) [4] is important in maintaining normal levels of oxygen free radicals. Mutations in the CuZn-SOD gene (SOD1) have been found in 20% of familial MND patients, and at a lower frequency, in apparently sporadic MND cases [5,6]. We have reported on two mutations in MND patients from Russia [7].

      Detoxification processes might produce free radicals which can become transformed into nontoxic products. These processes play a key role in metabolism of xenobiotics, in­cluding most therapeutic drugs and environmental pollutants [8], many of which may be involved in the degeneration of neuronal cells. Detoxification of xenobiotics included their activation during phase I and deactivation of highly toxic intermediate metabolic products during phase II. The cyto­chrome P-450 (CYP) (phase I) and glutathione-S-transferase (GST) supergene families and arylamine N-acetyltransferase type 2 (NAT2) (phase II) play major roles in these biotrans­formation processes.

      The CYPs are responsible for the oxidative, peroxidative and reductive metabolism of endogenous and exogenous compounds. Alterations in CYP activity can render individ­uals susceptible to the actions of endogenous and of exo­genous environmental toxins. CYP2E1, CYP2D6, CYP2A1, and CYP1A2, may be involved in pathogenesis of neuro­logical diseases [9-11].

      The CYP2E1 (an ethanol-inducible cytochrome) cata­lyzes the oxidation of more than 75 xenobiotic substrates and has the unique ability to activate many xenobiotic compounds into toxic metabolites that often free radicals and have been proposed to underlie pathogenesis of amyotrophic lateral sclerosis (ALS) [3]. Recently, a 96 bp insertion polymor­phism (CYP2E1*1D) in the CYP2E1 promoter was localized to a region between –2270 and –1672. Genotypes containing the insertion are associated with higher levels of induced enzyme activity than is the wild type [12]. This increase prob­ably elevate the formation of reactive oxygen species and of neurotoxic metabolites. We assume that this polymorphism was associated with an increased risk of MND.

      Debrisoquine 4-hydroxylase (CYP2D6) involved in the metabolism of a wide range of xenobiotics. Approximately 5-10% of Caucasians are deficient in this enzyme activity [“poor metabolizer” (PM) phenotype] [13]. This phenotype has been associated with various diseases, including Parkin­son’s disease [14] and Alzheimer’s disease [15]. Of at least 30 different defective CYP2D6 alleles, six contribute to 95-99% of PM phenotypes [13]. The well-characterized variant CYP2D6*4 results from a G→A substitution at the intron 3/ exon 4 junction. Homozygosity for CYP2D6*4 is genetically responsible for about 75% of PM phenotypes [16]. In one study, the frequency of CYP2D6*4 homozygotes among ALS patients did not differ from that of the control group [17]. In another study, there was a significant increase in the fre­quency of the CYP2D6*4 allele in the ALS patient group. This suggests that the CYP2D6*4 allele may be a risk factor for the development of ALS [10].

      Phase I detoxification metabolites are often potentially more harmful than the original compounds, and it is impor­tant that they do not accumulate. Phase II enzymes catalyze binding of intermediary metabolites and their transformation into hydrophilic excretable products. Thus, the GSTs mediate the conjugation of many electrophilic compounds with reduced glutathione (GSH) [18]. At least seven families of human soluble GST have been identified in humans: α, µ, π, δ, θ, κ , and ζ [19]; θ1 (GSTT1), µ1 (GSTM1) and π1 (GSTP1) are of greatest interest here. Deletion variants or null alleles of GSTT1 and GSTM1 genes fail to express a product. Homozygozity for null alleles of GSTT1 and GSTM1 genes are common, occurring in 10-20% and 40-65% of the Caucasian population, respectively [20]. The GSTP1 gene has several polymorphisms. The exon 5 A→G transition resulting in the Ile→Val substitution at codon 105, confers altered heat stability and specific activity of GSTP1 [21]. These variants are thought to increase susceptibility to chronic bronchitis, arteriosclerosis, various types of cancer [22], and neurological diseases [23].

      The NAT2 catalyze the N-acetylation of xenobiotics with a primary aromatic amine or a hydrazine structure (such as the toxic nitrosamines in tobacco smoke, antioxidants, and pesticides). It is also implicated in drug metabolism, including drug-drug interactions [24]. The population is divided in two main groups according to variation in NAT2 activity: slow acetylators (SA) and rapid acetylators (RA). The SA are homozygous for two recessive “slow” alleles and produce <20% on NAT2 activity compared to the wild type gene. The RA have at least one wild-type “fast” allele [25]. Many studies have demonstrated the influence of this acetylation polymorphism on the development of various diseases, including several types of cancer [26] and neurological dis­eases such as Parkinson’s disease [27].

      These data, and the fact that patients with chronic neuro­logical dysfunction, appear to have a reduced capacity to detoxify certain environmental compounds [28], suggest that genes of the detoxification system may be involved in MND pathogenesis. The aim of this study was to test this hypo­thesis. We carried out a comparative analysis of the distribu­tions of various genotypes of the CYP2E1, CYP2D6, GSTT1, GSTM1, GSTP1, and NAT2 genes in MND patients and con­trol subjects.