• CYP2D6 links PD risk to pesticide detoxification and brain dopamine synthesis. • CYP2E1 bioactivates MPTP-like toxins and drives dopamine-derived oxidative stress. • Cholesterol 24-hydroxylase CYP46A1 modulates α-syn pathology. CYP2D6 links PD risk to pesticide detoxification and brain dopamine synthesis. CYP2E1 bioactivates MPTP-like toxins and drives dopamine-derived oxidative stress. Cholesterol 24-hydroxylase CYP46A1 modulates α-syn pathology. This review synthesizes three decades of evidence regarding the role of cytochrome P450 enzymes (CYPs) in Parkinson’s disease (PD), revealing their multifaceted roles beyond traditional pesticide metabolism. While CYP2D6 remains the most studied enzyme due to its association with PD risk in poor metabolizer phenotypes and its dual role in dopamine (DA) synthesis (directly via tyramine hydroxylation and indirectly through precursor demethylation), recent research has highlighted less-studied CYPs with critical pathological implications. Another focal enzyme, CYP2E1, mediates the bioactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to its neurotoxic metabolite, 1-methyl-4-phenylpyridinium, thereby inducing oxidative stress. It also partially contributes to DA oxidation, a process that generates multiple cytotoxic byproducts. These toxic products are implicated in two major pathological processes involved in the development of PD—oxidative stress and protein misfolding—which adversely affect dopaminergic neurons. Additionally, CYP3A4 converts acetaminophen to N-acetyl-p-benzoquinone imine in the substantia nigra, contributing to dopaminergic neuron loss. Emerging enzymes like CYP7B1 (which reduces midbrain DA neuron survival via 7α,26-dihydroxycholesterol) and CYP46A1 (inhibiting α-synuclein aggregation) further expand the involvement of the CYP network in PD. The CYP4 family has also emerged as regulators of fatty acid and eicosanoid metabolism, linking to neuroinflammation and oxidative stress. While CYP2D6 and CYP2E1 have dominated prior studies, this review underscores the broader impact of the CYP superfamily on PD pathogenesis through interconnected pathways involving xenobiotic detoxification, fatty acid homeostasis, cholesterol clearance, and neuroinflammation. By integrating these diverse mechanisms, this study establishes a multifactorial framework that connects CYP-mediated biochemical cascades to PD pathogenesis. This article addresses the role of various Cytochrome P450 enzymes (CYPs) in Parkinson’s disease (PD), covering both their biochemical functions and how genetic, epigenetic, and environmental factors influence PD progression. Recent findings on CYPs, particularly CYP2D6 and CYP2E1, and their involvement in PD pathogenesis through mechanisms such as pesticide metabolism, dopamine synthesis, and oxidative stress, are summarized. We also explore the contribution of lesser-studied CYPs, like CYP46A1 and CYP39A1, in cholesterol and fatty acid metabolism, presenting novel insights for therapeutic development. The review additionally touches on the influence of CYPs on disease biomarkers and therapeutic strategies, which may hold potential for both clinical application and personalized treatment of PD. Unlike prior reviews focused on CYP2D6 and CYP2E1, this work consolidates evidence for a broader CYP network in PD, highlighting novel therapeutic targets in cholesterol and fatty acid metabolism pathways.
Ren et al. (Sun,) studied this question.