Trends in Pharmacological Sciences
Parkinson's disease, pesticides and individual vulnerability
Section snippets
Chemical aspects: the dual nature of all XMEs and the wide variety of alternative metabolic pathways
XMEs constitute a battery of enzymes (or enzyme-related systems) that play a central role in the response of cells to ‘stress’ chemicals by catalysing detoxicating or toxicating reactions. Unfortunately, the complexity of their molecular mechanisms is often ignored. The conventional distinction between universally harmful ‘activating’ (i.e. phase I) XMEs and universally beneficial ‘detoxificating’ (phase II or III) XMEs is now irrevocably dated. Any XME can either activate or detoxify different
Innate genetic aspects: individual combinations of XME polymorphisms
Another important set of variables in the metabolism of xenobiotics is related to the infinite number of possible combinations of human genetic XME polymorphisms that contribute to our so-called ‘metabolic fingerprint’.
Polymorphic phase I human XMEs include many cytochrome P450 enzymes (CYP1A1, 1A2, 1B1, 2A6, 2A13, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, 3A4, 3A5, 3A7, 4B1, 5A1, 8A1 and 21), flavin-containing monooxygenase 3, MAO, paraoxonase, epoxide hydrolase, NAD(P)H:quinone oxido-reductase,
Acquired aspects: individual XME gene expression
The acquisition of modifications to the expression of individual genes encoding XMEs also inevitably affects the metabolism of different xenobiotics. Within the cell, xenobiotics can bind to specific cytosolic ‘xenosensors’ and induce (either specifically or nonspecifically) signal transduction events that can lead to different physiological and pharmacological responses, including cell homeostasis, proliferation, differentiation, apoptosis or necrosis [39]. The function of XMEs is highly
A preliminary working model
Taken together, the three sets of variables (chemical, innate and acquired) outlined above suggest a preliminary model that can help to explain the almost infinite variety of personal XME modulations present in real-life situations. Acquired modulation of XME gene expression will be determined by both lifestyle and dietary factors (e.g. smoking, drinking, consumption of meat and vegetables and consumption of drugs) and characteristic environmental and workplace exposures (including rural-living
Implications for susceptibility studies
We have advanced the hypothesis that PD-related vulnerability to pesticides is linked to a strictly personal ‘chemico–genetic XME blend’. In summary, our innate XME genetic fingerprints undergo acquired ‘modulations’, which in turn are influenced by an almost infinite variety of individual exposures to chemical mixtures of environmental pollutants. These modulations will occur in relation to the dual detoxicant–toxicant nature of each XME. Eventual biotransformation outcomes will also be
Prospects for the future
Analysis of complete individual XME phenotypes is not currently feasible. However, the effects of potential up- and downregulators of genes encoding XMEs in addition to typical direct XME inhibitors (e.g. grapefruit juice toward CYPs or alcohol toward GSTP1) make measurement of functional parameters (the phenotype of interest) highly desirable. The few available multiple analyses (e.g. cocktail strategy) seem to be inadequate for this purpose. Nevertheless, advances in biotechnology should
Acknowledgements
This work was supported by an Alma Mater Studiorum–University of Bologna grant. We are grateful to Robin M.T. Cooke for scientific editing.
References (45)
Environmental factors in Parkinson's disease
Neurotoxicology
(2002)Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat
Neurobiol. Dis.
(2002)Developmental exposure to the pesticides paraquat and maneb and the Parkinson's disease phenotype
Neurotoxicology
(2002)Pesticides directly accelerate the rate of alpha-synuclein fibril formation: a possible factor in Parkinson's disease
FEBS Lett.
(2001)Selective effects of insecticides on nigrostriatal dopaminergic nerve pathways
Neurotoxicology
(2002)Genetic susceptibility and the occurrence of Parkinson's disease
Parkinsonism Relat. Disord.
(1999)Environmental risk factors of young onset Parkinson's disease: a case-control study
Clin. Neurol. Neurosurg.
(2002)Environmental risk factors and Parkinson's disease: a meta-analysis
Environ. Res.
(2001)- et al.
Pitfalls of enzyme-based molecular anticancer dietary manipulations: food for thought
Mutat. Res.
(2003) Comments on the history and importance of aromatic and heterocyclic amines in public health
Mutat. Res.
(2002)
Variability in human metabolism of arsenic
Environ. Res.
Glutathione S-transferase M1, T1, and P1 polymorphisms and Parkinson's disease
Neurosci. Lett.
Etiology of Parkinson's disease
Can. J. Neurol. Sci.
Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP
Proc. Natl. Acad. Sci. U. S. A.
Recent advances in the genetics and pathogenesis of Parkinson disease
Neurology
Age-environment and gene-environment interactions in the pathogenesis of Parkinson's disease
Rev. Environ. Health
Genetics of Parkinsonism: a review
Ann. Hum. Genet.
Organochlorine insecticides in substantia nigra in Parkinson's disease
J. Toxicol. Environ. Health A
Familial and environmental risk factors in Parkinson's disease: a case-control study in north-east Italy
Acta Neurol. Scand.
Parkinsonism and occupational exposure to pesticides
Occup. Environ. Med.
Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease
J. Am. Med. Assoc.
Complete genomic screen in Parkinson disease: evidence for multiple genes
J. Am. Med. Assoc.
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2011, Ecotoxicology and Environmental SafetyCitation Excerpt :Nevertheless, the altered enzyme activities deserve further investigation. We have previously demonstrated that low amounts of Cu released from intrauterine devices could have a role in neurological or cardiovascular illnesses (Arnal et al., 2010a) and that there is a clear correlation between Cu homeostatic changes and neurological disorders in humans (Paolini et al., 2004; Pope et al., 2008; Arnal et al., 2010b). The tendency to over-express CRP and/or MTs to protect cells from the pro-oxidant status induced by transition metals has been reported by other authors (Zhou et al., 2004; Mocchegiani et al., 2005; Zatta et al., 2008).