Acetaminophen Overdose as a Potential Risk Factor for Parkinson's Disease

Abstract

Four complementary approaches were used to investigate acetaminophen overdose as a risk factor for Parkinson's disease (PD). Circulating microRNAs (miRNAs) serum profiles from acetaminophen-overdosed patients were compared with patients with terminal PD, revealing four shared miRNAs. Similarities were found among molecular structures of dopamine (DA), acetaminophen, and two known PD inducers indicating affinity for dopaminergic transport. Potential interactions between acetaminophen and the human DA transporter were confirmed by molecular docking modeling and binding free energy calculations. Thus, it is plausible that acetaminophen is taken up by the dopaminergic transport system into the substantia nigra (SN). A ChEMBL query identified proteins that are similarly targeted by DA and acetaminophen. Here, we highlight CYP3A4, present in the SN, a predominant metabolizer of acetaminophen into its toxic metabolite N-acetyl-p-benzoquinone imine and shown to be regulated in PD. Overall, based on our results, we hypothesize that overdosing of acetaminophen is a potential risk factor for parkinsonism.

Figure 1

Similarities between molecular structures. Similarities between molecular structures of dopamine (DA), acetaminophen (APAP), 1‐methyl‐4‐phenylpyridinium MPP ⁺, Paraquat, and methamphetamine (METH) were evaluated using the Tanimoto coefficient. https://pubchem.ncbi.nlm.nih.gov/score_matrix/score_matrix.cgi

Figure 2

Molecular docking modeling of dopamine (DA) (orange) and acetaminophen (purple) to DA transporter (DAT; represented by dark grey structure, key residues are colored by green) protein using Schrödinger Glide software. Binding pose of (a) DA and (c)acetaminophen to DAT; 2D interaction diagram of (b) DA and (d) acetaminophen with DAT. DA binds to DAT by formation of H‐bonds at ASP121, ALA117 and water molecule sites, and pi‐pi stacking with PHE325; acetaminophen binds to DAT by formation of H‐bonds at ASP121 site, and pi‐pi stacking at PHE325, TYR124 sites. Analysis of the interaction patterns reveals that ASP121 and ALA117 serve as H‐bonds acceptors and water serves as H‐bond donor.

Figure 3

Common human protein targets for dopamine (DA) and acetaminophen (APAP) based on a ChEMBL human protein target search. Forty‐five protein targets appear in common between DA and APAP.