Dolutegravir Increased Mortality Rate, Climbing Deficits and Altered Biomarkers of Oxidative Injury in Harwich Drosophila melanogaster

Background and Objective: Dolutegravir (DTG) is safer compared to Efavirenz (EFV) as a component of antiretroviral combination therapy.However, recent studies suggested that DTG might be associated with oxidative stress toxicity in humans.This study intended to assess whether a non-target organism, Drosophila melanogaster, could replicate the DTG-induced oxidative stress and to determine the potential toxicity of a finished dolutegravir product because of possible environmental contamination.Materials and Methods: Flies (mixed sexes) were exposed to a series of ten DTG concentrations (0-50 mg per 10 g fly food) for a 7 days LD 50 determination, followed by a 28 days survival assay, then a 5 days treatment to evaluate the effects of the test drug on negative geotaxis, fertility and some antioxidant biomarkers.Also, in silico molecular docking was performed to predict the possible molecular interactions of Drosophila acetylcholinesterase (AChE) and glutathione-S-transferase (GST) enzymes with the test drug.Results: The LD 50 of DTG in D. melanogaster was 16.53 mg/10 g of food.The DTG showed a significant (p<0.05)reduction in 28 days survival and climbing ability as well as alterations in the levels of biochemical markers [total thiols (T-SH), AChE, GST, catalase (CAT), superoxide dismutase (SOD) and malondialdehyde (MDA)] of the exposed flies.The test drug interacted with similar amino acid residues with a significantly (p<0.05)higher molecular attraction for the active sites of GST but a lower (p>0.05)binding affinity for those of AChE compared to the respective natural substrates and standard inhibitors.Conclusion: Oral administration of DTG in D. melanogaster significantly increased mortality rate, climbing and antioxidant deficits through a competitive antagonism of GST and AChE activities.The DTG-induced oxidative stress was replicated in the flies.Thus, environmental contamination with dolutegravir sodium could adversely affect non-target organisms in an ecosystem.