Reproductive and Oxidative Stress Toxicity of Dolutegravir-Based Combination Antiretroviral Therapy in Drosophila melanogaster

Iorjiim, Walter Mdekera; Omale, Simeon; Bagu, Great David; Gyang, Steven Samuel; Alemika, Taiwo E.

doi:10.9734/jamps/2020/v22i630177

Cited by 3 publications

(5 citation statements)

References 39 publications

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“…The exposure of DTG-HAART naïve D. melanogaster showed a significant (P<0.001) reduction in emergence without eclosion failure. This observation implies that DTG-HAART may have altered more overwhelmingly the reproductive capacity in the exposed adult flies than the developmental toxicity at the eclosion stage [27].…”

Section: Discussionmentioning

confidence: 97%

Effects of Dolutegravir (DTG) on Survival, Pupariation and Emergence in Drosophila melanogaster: The Rescue Role of Brassica oleracea

Leritshimwa

Awadzi

Kennedy

et al. 2022

EJMP

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The study aimed at determining the protective role of Brassica oleracea on dolutegravir-induced changes in Pupariation and Emergence of Drosophila melanogaster. D. melanogaster aged 3-5 days old were exposed to different concentrations (0.5 to 4 mg/ 5 g diet) of dolutegravir and B. oleracea extract (7.5–1000 mg/5 g diet) for 7 days to determine the lethal concentration (LC50). D. melanogaster were then exposed to the extract (50, 100, 200, and 400 mg/5 g diet) and controls (diet alone and vitamin C) to assess their effects on pupariation and emergence. A 14-day assay was also performed to evaluate the effect of the extract and toxicant (dolutegravir) on fly survival. The result showed a dose-dependent significant decrease (P < 0.05) and a dose-dependent significant increase (P < 0.05) in survival for D. melanogaster exposed to dolutegravir and the extract respectively, when compared to the control group. Results showed a delay in pupariation and decrease in mean pupariation in flies exposed to dolutegravir alone. An improvement in the same parameters was observed in D. melanogaster pre-treated with the extract before exposure to dolutegravir. D. melanogaster pre-treated with 200 and 400 mg extract per 5 g diet showed emergence that was comparable to those in the control groups. A significant decrease (P < 0.05) was observed in the groups exposed to 50 and 100 mg extract per 5 g diet, suggesting no protection at these doses. This study concludes that B. oleracea leaf extract, at certain concentrations, is able to protect against dolutegravir-induced changes in pupariation and emergence in D. melanogaster.

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Section: Discussionmentioning

confidence: 97%

Effects of Dolutegravir (DTG) on Survival, Pupariation and Emergence in Drosophila melanogaster: The Rescue Role of Brassica oleracea

Leritshimwa

Awadzi

Kennedy

et al. 2022

EJMP

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“…Also, the composition of the reaction mixture, the incubation conditions and the wavelength for absorbance measurement were all as described by Abolaji et al 29 . Total thiol content was calculated using (g) = 9.6 mMG 25 , was followed to determine SOD activity.…”

Section: Study Area: This Research Work Was Carried Out In January Tomentioning

confidence: 99%

“…Also, the reaction compositions and wavelength used to measure absorbance for SOD activity calculation were as defined by Iorjiim et al 25 . The CAT activity was measured using Aebiʼs method described by Abolaji et al 29 25 . All experimental conditions were as published by Iorjiim et al 25 .…”

Section: Study Area: This Research Work Was Carried Out In January Tomentioning

confidence: 99%

“…The CAT activity was measured using Aebiʼs method described by Abolaji et al 29 25 . All experimental conditions were as published by Iorjiim et al 25 .…”

Section: Study Area: This Research Work Was Carried Out In January Tomentioning

confidence: 99%

“…The administration method chosen for this investigation was to mix the test drug with a tasty substrate like sucrose or brewerʼs yeast-supplemented fly diet 22 to improve palatability 23 . This model organism has been successfully used to assess antiretroviral drug-induced genotoxicity 24 and antioxidant deficits 25 . In this study, the toxic potentials of DTG in terms of mortality rate, fertility, climbing performance (acetylcholinesterase activity and negative geotaxis) and some parameters of the antioxidant system on the Harwich strain of Drosophila melanogaster were investigated.…”

Section: Introductionmentioning

confidence: 99%

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

Iorjiim¹,

Omale²,

Bagu³

et al. 2023

J. of Pharmacology and Toxicology

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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.

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Involvement of functional senescence in efavirenz-induced toxicity in fruit fly

Iorjiim,

Omale,

Ede

et al. 2023

Toxicology Research

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Background We aimed in this article to assess the likeliness of efavirenz to induce functional senescence in Drosophila melanogaster (fruit fly). Methods Ten different concentrations of EFV were mixed with fly food and fed to 3-day-old flies orally for a 7 day LC50 calculation. Drug concentrations from LC50 were selected for a 28 day survival to determine the duration of treatment for behavioral and biochemical assays. A 5day feeding plan was used to investigate the effects of the drug on organismal, neuromuscular, reproductive, and metabolic senescence. An in silico study was executed to decipher a molecular interaction of Drosophila enzymes glutathione-s-transferase (GST) or acetylcholinesterase (AChE) with EFV. Results The calculated LC50 of EFV was 118 mg/10-g fly diet. The test drug induced a significant (P < 0.05) increase in fly mortality, climbing difficulty, and procreative deficits after a 5 day oral exposure. Similarly, there were significant (P < 0.05) biochemical alterations, which suggested in vivo biochemical damage against total thiols (T-SH), SOD (superoxide dismutase), CAT (catalase), GST, AChE, and MDA (malondialdehyde) in the test flies compared to the control groups. In silico study revealed a significantly (P < 0.05) higher binding energy between EFV and the active amino acids of fly AChE and GST when compared to the substrates or standard inhibitors respectively. Conclusion EFV exhibited ecotoxic potentials evidenced by age-related deficits in the fly’s functional integrity such as sluggish movement, procreative deficiency, increased mortality, and oxidant-antioxidant inequality. Results from in silico study suggested antagonism against GST and AChE activities as a likely mechanism of EFV-induced toxicity in the fruit fly.

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Reproductive and Oxidative Stress Toxicity of Dolutegravir-Based Combination Antiretroviral Therapy in Drosophila melanogaster

Cited by 3 publications

References 39 publications

Effects of Dolutegravir (DTG) on Survival, Pupariation and Emergence in Drosophila melanogaster: The Rescue Role of Brassica oleracea

Effects of Dolutegravir (DTG) on Survival, Pupariation and Emergence in Drosophila melanogaster: The Rescue Role of Brassica oleracea

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

Involvement of functional senescence in efavirenz-induced toxicity in fruit fly

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