CYP2D6 polymorphism, pesticide exposure, and Parkinson's disease

Abstract

We performed a case-control study of Parkinson's disease (PD) in a population characterized by a high prevalence of pesticide exposure and studied the joint effect of pesticide exposure and CYP2D6. Although they are based on a small group of subjects with the joint exposure, our findings are consistent with a gene-environment interaction disease model according to which (1) pesticides have a modest effect in subjects who are not CYP2D6 poor metabolizers, (2) pesticides' effect is increased in poor metabolizers (approximately twofold), and (3) poor metabolizers are not at increased PD risk in the absence of pesticide exposure.

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

“…In rats, phenobarbital treatment induces brain CYP2B1, and also potentiates the neurotoxic effects of the anticancer substrate 9-methoxy-N-(2)-methylellipticinium acetate (Upadhya et al, 2002); in situ neurotoxin activation may have implications in neurodegenerative diseases. 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).…”

“…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).…”

“…These isozymes can metabolize a vast array of compounds including centrally acting drugs, neurotoxins, neurotransmitters, and neurosteroids (Ekins and Wrighton, 1999;Hiroi et al, 2001;Elbaz et al, 2004;Zanger et al, 2004;Seliskar and Rozman, 2007). Individuals respond differently to centrally acting therapeutic drugs, and their response is not always predicted by circulating drug levels in their plasma (Michels and Marzuk, 1993).…”

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

“…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].…”

The neurotoxicology of hard foraging and fat-melts

“…30). In view of the increasing popularity of fat-decreasing diets, it is sobering to consider that blood PCB levels increase during chronic weight loss (31, Genetics may also figure here, because carriers of the CYP2D6 allele associated with ''poor catabolism'' of organochlorines show a higher prevalence of Parkinson's disease (34,35). More generally, the development of strategies to optimize diet and body composition for long-term health of blood vessels and the brain may be guided by many loci in an individual's genotype.…”