Further evidence that interactions between CYP2D6 and pesticide exposure increase risk for Parkinson's disease

Deng, Yifu; Newman, Beth; Dunne, Michael P.; Silburn, Peter A.; Mellick, George D.

doi:10.1002/ana.20143

Cited by 53 publications

(30 citation statements)

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“…CYP2D6 (McCann et al, 1997;Elbaz et al, 2004) has been implicated in Parkinson's disease; this enzyme may play a role in activating or inactivating putative toxins that are associated with Parkinson's disease (Suzuki et al, 1992;Gilham et al, 1997;Vaglini et al, 2004;Viaggi et al, 2007). Individuals with genetically deficient CYP2D6 are at an increased risk for Parkinson's disease, especially when exposed to environmental neurotoxins (Deng et al, 2004;Elbaz et al, 2004). Cigarette smoking reduces the risk for Parkinson's disease (Allam et al, 2004;Galanaud et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Brain Drug-Metabolizing Cytochrome P450 Enzymes are Active In Vivo, Demonstrated by Mechanism-Based Enzyme Inhibition

Miksys

Tyndale

2008

Neuropsychopharmacol

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Individuals vary in their response to centrally acting drugs, and this is not always predicted by drug plasma levels. Central metabolism by brain cytochromes P450 (CYPs) may contribute to interindividual variation in response to drugs. Brain CYPs have unique regional and cell-type expression and induction patterns, and they are regulated independently of their hepatic isoforms. In vitro, these enzymes can metabolize endogenous and xenobiotic substrates including centrally acting drugs, but there is no evidence to date of their in vivo function. This has been difficult to demonstrate in the presence of hepatically derived metabolites that may cross the blood-brain barrier. In addition, because of the membrane location of brain CYPs and the rate limiting effect of endogenous heme levels on the activity and appropriate membrane insertion of some induced CYPs, it has been unclear whether sufficient cofactors and coenzymes are present for constitutive and induced CYP forms to be enzymatically active. We have developed a method using a radiolabeled mechanism-based inhibitor of CYP2B1, 3 H-8-methoxypsoralen, to demonstrate for the first time that both the constitutive and induced forms of this enzyme are active in situ in the living rat brain. This methodology provides a novel approach to assess the function of enzymes in extrahepatic tissues, where expression levels are often low. Selective induction of metabolically active drug metabolizing enzymes in the brain may also provide ways to control prodrug activation in specific brain regions as a novel therapeutic avenue.

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Section: Discussionmentioning

confidence: 99%

Brain Drug-Metabolizing Cytochrome P450 Enzymes are Active In Vivo, Demonstrated by Mechanism-Based Enzyme Inhibition

Miksys

Tyndale

2008

Neuropsychopharmacol

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“…A French study [274] reported that risk of PD for professional pesticide use was more than doubled in slow metabolizers compared to other individuals, whereas, in the absence of pesticide exposure, slow metabolizers had no increased risk [274]. These results were supported by an Australian study [275] but not by a European multicentre study [276].…”

Section: Susceptibility Genesmentioning

confidence: 98%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…Most cases are sporadic, and exposure to environmental or endogenous toxins, with or without a genetic predisposition, is thought to play a large role in these cases. 115 There is evidence that individuals with a CYP2D6 poor metabolizer genotype are at greater risk for this disease and that this risk is even greater with exposure to neurotoxic pesticides. 116,117 CYP2D6 metabolizes and inactivates a number of compounds that can cause parkinsonian symptoms, including MPTP, parathion, iso quin o line and β-carbolines.…”

Section: Neurotoxicitymentioning

confidence: 99%