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
The effect of the extract of Cucumis metuliferus fruit on some male reproductive parameters was investigated in albino rats. The LD50 of the extract was above 5000 mg/kg body weight when administered orally. Histological studies showed that there was no remarkable change in the testes histology compare to the control. The effects on sperm cells showed a statistically significant (P0.05) increase in total sperm count with an insignificant (P0.05) increase in viability count in rats treated with 500 mg/kg dose point. On the other hand; 1000 mg/kg dose point produced significant (P0.05) decrease in total sperm count and viability count compare to control. This result suggests that C. metuliferus fruit extracts could be beneficial in increasing sperm/semen integrity
