Avaliação da farmacocinética, citotoxicidade e genotoxicidade do éter n-butil dilapiol, candidato a larvicida contra Aedes aegypti e Aedes albopictus, Manaus, AM

Abstract

n-butyl ether dillapiole (EBD) is a semi-synthetic derivative of dilapiol, a major component found in the essential oil of Piper aduncum. This compound has showed potential insecticidal effects against Aedes aegypti and Aedes albopictus mosquitoes, making it a possible alternative for controlling these mosquitoes, which are vectors of various arboviruses, including the agents of dengue, a disease of significant epidemiological importance. However, studies on the toxic effects of this substance on mammals and other vertebrates are scarce. The aim of this study was to evaluate the toxicity of semi-synthetic EBD and its metabolites in in vivo and in silico models. In this context, in silico predictions were carried out to evaluate pharmacokinetic and toxicity parameters. Biochemical and histopathological alterations were assessed in peripheral blood and liver, respectively, of male Balb/C mice. The genotoxic effect of the EBD was evaluated in male Balb/C mice through comet assay in peripheral blood and micronucleus test in bone marrow cells. The study of the EBD in silico in Balb/C mice exhibited immunotoxic and nephrotoxic activity, high intestinal absorption, and low permeability through the skin and blood-brain barrier. Biochemical analyses showed slight changes in renal filtration and hepatic metabolism at the lowest concentrations (10 and 20 mg/kg). Histopathological analyses did not show severe damage to liver tissues, and at the highest concentration (40 mg/kg), there was a process of hepatic protection. The comet assay detected an increase in the induction of primary DNA damage (genotoxic effect) at the highest concentration (40 mg/kg). The micronucleus test revealed mutagenic and cytotoxic effects at a concentration of 40 mg/kg. Semi-synthetic EBD proved to be relatively safe, since it may offer low risks to human health and other non-target organisms. However, further investigations are needed to understand the molecular mechanisms underlying liver adaptive responses in Balb/C mice, in addition, the increase in cytogenotoxic effects in Balb/C mice and to assess their long-term effects.