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Cytochrome P450 2D6 and Parkinson’s Disease: Polymorphism, Metabolic Role, Risk and Protection

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Abstract

Cytochrome P450 (CYP) 2D6 is one of the most highly active, oxidative and polymorphic enzymes known to metabolize Parkinsonian toxins and clinically established anti-Parkinson’s disease (PD) drugs. Albeit CYP2D6 gene is not present in rodents, its orthologs perform almost the similar function with imprecise substrate and inhibitor specificity. CYP2D6 expression and catalytic activity are found to be regulated at every stage of the central dogma except replication as well as at the epigenetic level. CYP2D6 gene codes for a set of alternate splice variants that give rise to a range of enzymes possessing variable catalytic activity. Case-control studies, meta-analysis and systemic reviews covering CYP2D6 polymorphism and PD risk have demonstrated that poor metabolizer phenotype possesses a considerable genetic susceptibility. Besides, ultra-rapid metabolizer offers protection against the risk in some populations while lack of positive or inverse association is also reported in other inhabitants. CYP2D6 polymorphisms resulting into deviant protein products with differing catalytic activity could lead to inter-individual variations, which could be explained to certain extent on the basis of sample size, life style factors, food habits, ethnicity and tools used for statistical analysis across various studies. Current article describes the role played by polymorphic CYP2D6 in the metabolism of anti-PD drugs/Parkinsonian toxins and how polymorphisms determine PD risk or protection. Moreover, CYP2D6 orthologs and their roles in rodent models of Parkinsonism have also been mentioned. Finally, a perspective on inconsistency in the findings and futuristic relevance of CYP2D6 polymorphisms in disease diagnosis and treatment has also been highlighted.

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Acknowledgements

Authors earnestly acknowledge the Department of Science and Technology, India and Council of Scientific and Industrial Research, India, respectively, for providing research fellowship to Mohd Sami ur Rasheed and Abhishek Kumar Mishra. The CSIR-IITR communication number of this article is 3454.

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  1. Toxicogenomics and Predictive Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India

    Mohd Sami ur Rasheed, Abhishek Kumar Mishra & Mahendra Pratap Singh

  2. Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, Uttar Pradesh, 226001, India

    Mohd Sami ur Rasheed, Abhishek Kumar Mishra & Mahendra Pratap Singh

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ur Rasheed, M.S., Mishra, A.K. & Singh, M.P. Cytochrome P450 2D6 and Parkinson’s Disease: Polymorphism, Metabolic Role, Risk and Protection. Neurochem Res 42, 3353–3361 (2017). https://doi.org/10.1007/s11064-017-2384-8

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