Analysis of the effects of manool, a diterpene of Salvia officinalis, on cell and genomic integrity.

Abstract

The Salvia genus is the largest in the Lamiaceae family, with more than 900 species, and Salvia officinalis is a species that has many therapeutic activities, such as anti-inflammatory, antimicrobial, eupeptic and anti-depressive. In addition, it is used in cooking as a condiment. In extracts of S. officinalis, terpenoids and phenolic compounds were identified as the main classes of special metabolites, with diterpenes being their most characteristic micrometabolites. Among these, manool stands out in the scientific literature as one of the most abundant components of essential oils and extracts of S. officinalis. Previous studies performed by our research group have shown the genotoxic effect of manool on cultures of V79 (Chinese hamster lung fibroblasts) and HepG2 (human hepatocarcinoma) cells. On the other hand, smaller non-genotoxic concentrations of this diterpene were able to reduce the genotoxicity of the methyl methanesulfonate mutagen in HepG2 cells, but not in V79 cells. Additionally, manool showed cytotoxic effect in different tumor cell lines, exhibiting significant selectivity. The present study aims to broaden the genotoxic evaluation necessary for drug candidates for human use through in vivo toxicogenic study and dosage of liver enzymes as a parameter of liver toxicity. In addition, different analyzes will be conducted aiming at a better understanding of the action of manool as its influence on the cell cycle and the cell death pathways, by flow cytometry; its effect on genotoxicity induced by mutagens with different mechanisms of action, such as doxorubicin, hydrogen peroxide and etoposide, using the micronucleus test; and the analysis of the expression of genes related to anti-inflammatory pathways (NF-ºB, nuclear factor kappa B), antioxidant (Nrf-2, nuclear factor erythroid 2 [NF-E2] -related factor 2, factor 2) and pro-apoptotic nuclear (TP53, tumor suppressor gene) by Western blot, as possible mechanisms involved in its action. The results obtained from the different biological evaluations will allow a better understanding of the action of manool on the organism, contributing to the safe and effective use in future therapeutic applications. (AU)