Isometamidium chloride alters redox status, down-regulates p53 and PARP1 genes while modulating at proteomic level in Drosophila melanogaster

Abstract

As trypanocide, several side effects have been reported in the use of Isometamidium chloride. This study was therefore, designed to evaluate its ability to induce oxidative stress and DNA damage using D. melanogaster as a model organism. The LC₅₀ of the drug was determined by exposing the flies (1–3 days old of both genders) to six different concentrations (1 mg, 10 mg, 20 mg, 40 mg, 50 mg and 100 mg per 10 g of diet) of the drug for a period of seven days. The effect of the drug on survival (28 days), climbing behavior, redox status, oxidative DNA lesion, expression of p53 and PARP1 (Poly-ADP-Ribose Polymerase-1) genes after five days exposure of flies to 4.49 mg, 8.97 mg, 17.94 mg and 35.88 mg per 10 g diet was evaluated. The interaction of the drug in silico with p53 and PARP1 proteins was also evaluated. The result showed the LC₅₀ of isometamidium chloride to be 35.88 mg per 10 g diet for seven days. Twenty-eight (28) days of exposure to isometamidium chloride showed a decreased percentage survival in a time and concentration-dependent manner. Isometamidium chloride significantly (p < 0.05) reduced climbing ability, total thiol level, Glutathione-S-transferase, and Catalase activity. The level of H₂O₂ was significantly (p < 0.05) increased. The result also showed significant (p < 0.05) reduction in the relative mRNA levels of p53 and PARP1 genes. The in silico molecular docking of isometamidium with p53 and PARP1 proteins showed high binding energy of −9.4 Kcal/mol and −9.2 Kcal/mol respectively. The results suggest that isometamidium chloride could be cytotoxic and a potential inhibitor of p53 and PARP1 proteins.

Keywords:

• Isometamidium chloride
• oxidative stress
• p53
• Poly (ADP-Ribose) polymerase-1
• Drosophila melanogaster

Acknowledgements

All thanks to the African Center of Excellence on Neglected Tropical Diseases and Forensic Biotechnology (ACENTDFB) for the funds and facilities provided to carry out the study. Our gratitude to Dr. Amos Abolaji of Department of Biochemistry University of Ibadan and his team for hosting us in his Laboratory to carry out the biochemical analyses aspect of this study.

Author contributions

Conception: AM, ADS, Design: AM, ADS and AG, Execution: All authors, Manuscript writing and proofreading: all authors.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data available statement

Data will be shared upon request.