ABSTRACT
BACKGROUND: Lamivudine and tenofovir disoproxil fumarate act against the replication of hepatitis B and human immunodeficiency viruses via inhibition of the reverse transcriptase enzyme activity, thereby preventing the synthesis of viral DNA. Chronic administration of these drugs has been associated with toxicities, including senescence, oxidative stress and premature death. A study of these toxicities in Drosophila melanogaster, which share 75% genomic similarity with humans could help to develop a pharmacologic intervention. METHODS: Susceptibility of D. melanogaster for lamivudine and tenofovir-induced toxicities were investigated. First, flies (≤3 days old) were fed with drugs-supplemented diet at varying concentrations (1mg to 300mg/10-gram diet) or distilled water for seven days to determine LD50. Secondly, five groups of 60 flies were fed with four concentrations of test drugs: 2.9mg, 5.82mg, 11.64mg and 23.28mg each per 10-gram diet for 28 days survival and lifespan assays. Then 5-day treatment plan was utilized to determine drugs toxicities on climbing ability and some biomarkers of oxidative stress. Finally, molecular docking was carried out using the Auto-dock vina mode to predict the biological interactions between the test drugs and D. melanogaster acetylcholinesterase (AChE) or glutathione-S-transferase (GST). RESULTS: The LD50 of lamivudine or tenofovir was 47.07 or 43.95mg/10g diet, respectively. Each drug significantly (P<0.05) reduced the survival rate, longevity and climbing performance of the flies dose-dependently. These drugs also altered levels of biochemical parameters: AChE, GST, superoxide dismutase (SOD), catalase (CAT), total thiol (T-SH), and malondialdehyde (MDA) of the flies significantly (P<0.05). In silico molecular analysis showed that the test drugs interacted with significantly (P<0.05) higher binding affinities at the same catalytic sites of D. melanogaster GST and AChE compared with substrates (glutathione or acetylcholine). CONCLUSION: The significant lamivudine and tenofovir-induced toxicities observed as increased mortality, climbing deficits and compromised antioxidant defence in D. melanogaster demands further research for possible pharmacological intervention.
Subject(s)
Antioxidants , Drosophila melanogaster , Animals , Humans , Acetylcholine/metabolism , Acetylcholinesterase/genetics , Acetylcholinesterase/metabolism , Antioxidants/pharmacology , Biomarkers , Catalase/genetics , Catalase/metabolism , DNA, Viral/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Glutathione , Glutathione Transferase/metabolism , Lamivudine/toxicity , Lamivudine/metabolism , Malondialdehyde/metabolism , Molecular Docking Simulation , Oxidative Stress , RNA-Directed DNA Polymerase/metabolism , Sulfhydryl Compounds , Superoxide Dismutase/metabolism , Tenofovir/toxicity , Tenofovir/metabolismABSTRACT
In this article, we aimed to investigate the anti-aging activity of Lantana camara ethanolic leaves-extract in Drosophila melanogaster: survival and longevity (life span). L. camara leaves were collected and washed thoroughly of sand particles, air-dried, ground, and extracted by the maceration method using ethanol as a solvent. Phytochemical screening was carried out. 168-hour LC50 was determined by exposing fruit flies to concentrations ranging from 5 to 5000 mg/10 g diet for 7-days. Twenty-eight-day survival and longevity studies were carried out by administering L. camara ethanolic leaves extract at 5, 10, and 20 mg/10 g diet to 1-3 days old fruit flies. Each concentration was replicated four times with 50 fruit flies each. The emergence rate of young fruit flies from eggs laid by fruit flies administered L. camara leaves-extracts were also carried out. The total yield of the extraction was determined to be 18%. Phytochemical analysis revealed the presence of alkaloids, Flavonoids, Phenol, steroids, cardiac glycosides, and carbohydrates. 168-hour LC50 of L. camara was also determined to be 1135 mg/10 g diet. L. camara significantly prolonged (P < 0.05) survival rate and extended (P < 0.05) D. melanogaster life span compared with control. L. camara significantly increased (P < 0.05) emergence rate of young fruit flies from eggs laid by fruit flies administered L. camara ethanolic leaves extracts. From the experimental results, it can be concluded that the ethanol extract of L. camara leaves extended the life span of D. melanogaster at these concentrations. Due to similarities of conserved genes between humans and fruit flies, the use of L. camara ethanolic leaves extract at these concentrations is safe and may be recommended as herbal medicine in humans.
