INTRODUCTION: Paracetamol (acetaminophen) is a widely used analgesic and antipyretic drug. Although safe at therapeutic doses, excessive use results in the accumulation of a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which induces oxidative stress by depleting glutathione and binding to cellular macromolecules. This may be particularly harmful in organisms with reduced oxidative stress resilience, such as those carrying PRKN gene mutations, which in humans are linked to early-onset autosomal recessive Parkinson’s disease (PD).

AIM(S): To evaluate the effects of paracetamol on a Drosophila melanogaster model of PD with a mutation in the orthologous park gene.

METHOD(S): Adult flies of three strains – park1 mutants, w1118 (genetic background control), and Canton-S (wild type) – were exposed to 100 mM paracetamol for 24 h or to 1 mM and 100 µM in chronic feeding. Assessment included survival, gene expression (via qPCR), locomotor performance, and dopaminergic neuron counts.

RESULTS: A single 24-hour exposure to 100 mM paracetamol significantly reduced survival in homozygous park1 flies but not in controls. Expression of detoxification and stress-response genes (GstD2, Sod1, Trxr1) and dopaminergic pathway genes (DAT, ple) was dysregulated in park1 mutants. No loss of dopaminergic neurons was observed in PAL, PPL1, PPL2, PPM1/2, or PPM3 clusters.

CONCLUSIONS: Paracetamol exposure, even short-term, exacerbates oxidative stress and dopaminergic dysfunction in genetically predisposed flies. These findings suggest increased susceptibility to common drugs in individuals with PRKN mutations, warranting caution in paracetamol use among vulnerable populations.

FINANCIAL SUPPORT: This work was supported by National Science Centre grant no. 2022/46/E/NZ3/00095.