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Polymorphisms of toxifying and detoxifying hepatic enzymes in amyotrophic lateral sclerosis
  1. R Bachus1,
  2. K Neubert2,
  3. I Roots2,
  4. J Prudlo3,
  5. J Brockmöller4,
  6. A C Ludolph5
  1. 1Department of Neurology, Humboldt University of Berlin, Germany
  2. 2Department of Clinical Pharmacology, Humboldt University of Berlin
  3. 3Department of Neurology, University of Homburg, University of Goettingen, Germany
  4. 4Department of Clinical Pharmacology, University of Goettingen
  5. 5Department of Neurology, University of Ulm, Germany
  1. Correspondence to:
 Professor A C Ludolph, Department of Neurology, University of Ulm, 89075 Ulm, Steinhövelstraβe 9, Germany;
 albert.ludolph{at}rku.de

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A contribution of hepatic enzymes responsible for detoxification and toxification of xenobiotics and endogenous compounds has been suspected to contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). We studied 12 potentially relevant enzymes in 150 ALS patients and 373 controls on the genetic level and could not detect any significant difference between both groups. These results strongly support a view that—in contrast with earlier observations—hepatic foreign compound metabolism does not contribute to the pathogenesis of ALS.

Genetic studies of familial ALS have yielded at least six chromosomal loci and two disease genes (“alsin” and superoxide dismutase 1).1–3 Mutations on the superoxide dismutase 1 initially suggested a role for free radicals in the disease process but recent results clearly argue for a gain of function mechanism. The mechanisms through which the mutant enzyme exerts toxicity and results in selective motor neuron death remain unclear. Although familial ALS accounts only for 2% of all cases, the findings on the DNA level demonstrate the significance of genetic factors.

In contrast, the cause of the sporadic form of ALS remains largely obscure. Basically, the aetiology of the disease is viewed as multifactorial with polygenic as well as ecological factors. Assuming an involvement of exogenous or endogenous toxic factors, an inter-individually different capacity for toxification or detoxification of endogenous compounds, xenobiotics including drugs could cause an inter-individually different susceptibility to develop ALS. Thus, respective enzymes and their encoding genes with functionally different alleles might be candidates for susceptibility genes for the sporadic form of ALS. Some earlier studies of the metabolic phenotype seemed to show an altered xenobiotic metabolism in ALS patients. For example, Heafield et al4 described 74% slow acetylators among 14 ALS patients compared with 60% in the normal population.

We investigated a number of different genes encoding for toxifying and detoxifying enzymes that have been suspected to be causually linked to ALS: arylamine-N acetyl-transferase (NAT2), the glutathione-S transferases (GSTs) M1 and T1, microsomal epoxide hydrolase (mEH) as well as the cytochrome P-450 enzymes (CYP) 1A1, 2E1, 2C19, and 2D6. For all these enzymes, well defined polymorphisms are known. All methods used have been described previously.5 Briefly, DNA was extracted from blood samples, PCR amplified by gene specific primers, and analysed by restriction fragment length polymorphisms (RFLP).

We analysed blood of 150 patients with the diagnosis of sporadic ALS according to the revised El Escorial criteria and 373 control patients recruited in three German centres (Berlin, Homburg/Saar, and Hannover). Control patients had non-neurological diagnoses and were of white origin. The mean age of the patients was 55.6 years. The ratio of men to women was 1.1:1. In 26.7% of the patients the disease was of bulbar, in 73.3% of spinal onset.

Our RFLP analysis could not reveal any significant over-representation of a polymorphism (table 1) that has been associated with an altered metabolism for the encoded enzymes in ALS patients. In contrast with our hypothesis, we found a significant over-representation of the GST M1*B allele with 24% in the patients group versus 15.3% in the control group and a significant under-representation of the CYP2E11019T mutation (table 1). However, in the absence of differences of activity between the isoenzymes GSTM1*A and GSTM1*B, the significance of the B-allelic over-representation among ALS patients remains uncertain. As the CYP2E1 has toxifying properties and the CYP2E11019T mutation is associated with an increased enzyme activity an under-representation in the ALS population is likely to be of minor significance.

Our results are in accordance with other genotype studies analysing the enzymes GSTM1, CYP2D6, CYP1A1 and NAT26 as well as NAT2 and CYP2D67 where no significant differences between patients and control groups were found. Using a substantially larger population of ALS patients and extending these studies for other toxifying and detoxifying enzymes, we have found no significant differences between patients and control groups for the glutathione-S transferase T1, the microsomal epoxide hydrolase, and the cytochrome P-450 enzymes 2E1 and 2C19.

We conclude from our data, that an involvement of the analysed toxifying and detoxifying enzymes in the pathogenesis of ALS is most unlikely.

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