title: Prediction of pharmacokinetic and toxicological parameters of a 4-phenylcoumarin isolated from geopropolis: In silico and in vitro approaches.
abstract: In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta™ and MetaDrug™ software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array. CNM did not pass all parameters of Lipinski's rule of five, with a predicted low oral bioavailability and high plasma protein binding, but with good predicted blood brain barrier penetration. CNM was predicted to show low affinity to cytochrome P450 family members. Furthermore, the predicted Ames test indicated potential mutagenicity of CNM. Also, the probability of toxicity for organs and tissues was classified as moderate and high for liver and kidney, and moderate and low for skin and eye irritation, respectively. The PCR array analysis showed that CNM significantly upregulated about 7% of all DNA damage-related genes. By exploring the biological function of these genes, it was found that the predicted CNM genotoxicity is likely to be mediated by apoptosis. The predicted ADME/Tox profile suggests that external use of CNM may be preferable to systemic exposure, while its genotoxicity was characterized by the upregulation of apoptosis-related genes after treatment. The combined use of in silico and in vitro approaches to evaluate these parameters generated useful hypotheses to guide further preclinical studies.
authors: Department of Physiological Sciences, Piracicaba Dental School, University of Campinas (UNICAMP), SP, Brazil; Molecular Targets Laboratory, National Cancer Institute (NCI), National Institute of Health (NIH), Frederick, MD, USA.
authors: Marcos Guilherme
authors: MG
authors: da Cunha
authors: Department of General Biology, Laboratory of Physiology and Pathophysiology, State University of Ponta Grossa, Ponta Grossa, PR, Brazil.
authors: Gilson César Nobre
authors: GC
authors: Franco
authors: Department of Physiological Sciences, Piracicaba Dental School, University of Campinas (UNICAMP), SP, Brazil.
authors: Marcelo
authors: M
authors: Franchin
authors: Molecular Targets Laboratory, National Cancer Institute (NCI), National Institute of Health (NIH), Frederick, MD, USA.
authors: John A
authors: JA
authors: Beutler
authors: Department of Agri-Food industry, Food and Nutrition, "Luiz de Queiroz" College of Agriculture, University of São Paulo (USP), Piracicaba, SP, Brazil.
authors: Severino Matias
authors: SM
authors: de Alencar
authors: College of Pharmaceutical Sciences, Federal University of Alfenas, Minas Gerais, Brazil.
authors: Masaharu
authors: M
authors: Ikegaki
authors: Department of Physiological Sciences, Piracicaba Dental School, University of Campinas (UNICAMP), SP, Brazil. Electronic address: rosalen@fop.unicamp.br.
authors: Pedro Luiz
authors: PL
authors: Rosalen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D001812:Blood-Brain Barrier / Q000378:metabolism; D003198:Computer Simulation; D003374:Coumarins / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007509:Irritants / Q000633:toxicity; D009152:Mutagenicity Tests; D011429:Propolis / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D003374:Coumarins; D007509:Irritants; C094411:4-phenylcoumarin; D011429:Propolis
keywords: Coumarin; Genotoxicity; Geopropolis; In silico; Pharmacokinetics; in vitro