Glutathione transferase polymorphism and Parkinson's disease

Abstract

Authors' reply Sir—We agree that the role of xenobiotic metabolising enzymes in the pathogenesis of disease is complex. As Moreno Paolini and colleagues state, these enzymes may either activate or detoxify disease-producing toxins, although we presume that they evolved mainly for the latter task. Irrespective of teleology, the most likely mechanism for the association between polymorphisms in xenobiotic metabolising genes and Parkinson's disease is altered metabolism of-neurotoxins. Pesticides are thought to be neurotoxic on the basis of epidemiological studies of Parkinson's disease, and experimental studies indicate that pesticides are mostly detoxified by glutathione transferases. However, as we had commented, pi class glutathione transferase (GSTP1-1) might activate pesticides. GSTP1-1 variants arise as a result of polymorphisms at two loci (bp105 and 114), and we noted an excess of heterozygotes in patients exposed to pesticides. Because GSTP1-1 is a dimer, heterozygous individuals will express both homodimers and heterodimers. How can the expression of all GSTP1-1 phenotypes confer increased susceptibility to an environmentally derived neurotoxin? We suggest that at least two sites on the toxin may need to be modified selectively by each of the GSTP1-1 variants to generate the final neurotoxin. This characteristic could identify the Parkinson's disease neurotoxin. Our study was small and hypothesis generating. Even so, the results emphasise the point that investigations of polymorphic xenobiotic metabolism enzymes and Parkinson's disease will only show an association in people exposed to neurotoxins unless, of course, the toxins are ubiquitous or the polymorphisms have effects unrelated to xenobiotic metabolism. Other associations have been reported with Parkinson's and polymorphisms in monoamine oxidase B in cigarette smokers,1Checkoway H Franklin GM Costa-Mallen P et al.A genetic polymorphism of MAO-B modifies the association of cigarette smoking and Parkinson's disease.Neurology. 1998; 50: 1458-1461Crossref PubMed Scopus (87) Google Scholar and CYP2D6 in individuals exposed to pesticides.2Hubble JP Kurth JH Glatt SL et al.Gene-toxin interaction as a putative risk factor for Parkinson's disease with dementia.Neuroepidemiology. 1998; 17: 96-104Crossref PubMed Scopus (39) Google Scholar Paolini and colleagues state that associations between polymorphic xenobiotic metabolising enzymes, in particular GSTP, and disease are inconsistent but have ignored many positive studies, some of which we had discussed. We believe that such associations may offer critical clues to the pathogenesis of Parkinson's disease. If polymorphisms in genes for xenobiotic metabolising enzymes alter risk of Parkinson's disease, then other non-genetic modulators of enzyme activity should similarly affect this risk. Thus, modulation of xenobiotic metabolism by cigarette smoking, diet, and organochlorine pesticides is a plausible mechanism for their effect on the risk of Parkinson's disease. The greatest risk factor for Parkinson's disease is old age, yet a mechanism for this association has been elusive.3Langston JW Epidemiology versus genetics in Parkinson's disease: progress in resolving an age-old debate.Ann Neurol. 1998; 44: S45-S52Crossref PubMed Scopus (163) Google Scholar Old age is associated with striking changes in xenobiotic and drug metabolism,4Le Couteur DG McLean AJ The aging liver: drug clearance and an oxygen diffusion barrier hypothesis.Clin Pharmacokinet. 1998; 34: 359-373Crossref PubMed Scopus (235) Google Scholar which provides logical explanation of the predisposition of elderly people to Parkinson's and possibly other diseases of old age. We have postulated that age-related changes in hepatic drug and xenobiotic metabolism are secondary to impaired oxygenation of hepatocytes (the oxygen diffusion barrier theory of ageing).4Le Couteur DG McLean AJ The aging liver: drug clearance and an oxygen diffusion barrier hypothesis.Clin Pharmacokinet. 1998; 34: 359-373Crossref PubMed Scopus (235) Google Scholar It should be possible to improve hepatic oxygenation with locally active and selective hepatic artery vasodilators, which could include low oral doses of prazosin, calcium channel blockers, nitrates, and even sildenafil. Glutathione transferase polymorphism and Parkinson's diseaseOver the past few-years one attractive hypothesis for the cause of Parkinson's disease has taken root: exogenous toxins damaging mitochondria of some neurons could cause the unfavourable cellular oxidative environment. Some studies show that Parkinson's disease is more common among people who report exposure to pesticides;1 however, since not all such individuals develop the disease, a genetic susceptibility mediated by the enzymatic mechanisms involved in the disposition of pesticides and other putative neurotoxins has been proposed. Full-Text PDF