p-synephrine induces transcriptional changes via the cAMP/PKA pathway but not cytotoxicity or mutagenicity in human gastrointestinal cells

ABSTRACT

p-Synephrine (SN) is an alkaloid added to thermogenic formulations for weight loss that is predominantly absorbed in the human gastrointestinal tract (GI). As the adverse effects of SN on GI cells remain unclear, the aim of present study was to examine whether SN affected cell viability, cell cycle kinetics, genomic stability, redox status, and expression of cAMP/PKA pathway genes related to metabolism/energy homeostasis in stomach mucosa (MNP01) and colon adenocarcinoma (Caco-2) human cells. p-Synephrine at 25–5000 μM was not cytotoxic to both cell lines. At 2–200 μM, SN increased the formation of reactive oxygen species (ROS) but also enhanced levels of antioxidant defense molecules glutathione (GSH) and catalase (CAT) activity, which may account for the absence of cytotoxicity/mutagenicity in both cell lines. SN induced expression of the cAMP/PKA pathway genes ADCY3 and MAPK1 in MNP01 cells and MAPK1, GNAS, PRKACA, and PRKAR2A in Caco-2 cells, as well as modulated the transcription of genes related to cell proliferation (JUN; AKT1) and inflammation (RELA; TNF) in both cell lines. Therefore, the improved antioxidant state mitigated pro-oxidative effects attributed to SN. Evidence indicates that SN does not appear to exhibit adverse potential but modulated the cAMP/PKA pathway in human GI cell lines.

KEYWORDS:

• Thermogenic supplements
• weight loss
• cAMP/PKA pathway
• micronucleus
• antioxidant defense

Acknowledgments

The authors thank Dr. Regislaine Valéria Burim, M.Sc. Lívia Cristina Hernandes, and Mrs. Joana D’arc Castania Darin for the technical assistance.

Authors’ contributions

Conceptualization and design: Ribeiro, D.L.; Antunes, L.M.G. Provision of study materials and funding acquisition: Antunes, L.M.G. Experiments execution and assembly of data: Ribeiro, D.L.; Machado, A.R.T.; Machado, C.S.; Aissa, A.F.; Dos Santos, P.W.; Data analysis and interpretation: Ribeiro, D.L.; Aissa, A.F.; Barcelos, G.R.M.; Antunes, L.M.G. Writing – original draft and editing: Ribeiro, D.L.; Machado, A.R.T.; Machado, C.S.; Aissa, A.F.; Dos Santos, P.W.; Barcelos, G.R.M.; Antunes, L.M.G. Supervision and project administration: Antunes, L.M.G.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This study was supported by the Coordination of Improvement of Higher Education Personnel – Brazil (CAPES) – Financing Code 001, São Paulo Research Foundation (FAPESP, grant no 2014/20344-9), Brazilian Innovation Agency (FINEP, grant no 01.09.0447.00), and National Council for Scientific and Technological Development (CNPq, grant no 141697/2014-8). L.M.G.A. thanks CNPq for the research productivity fellowship (grant no 302479/2019-8);Conselho Nacional de Desenvolvimento Científico e Tecnológico [Grant no 141697/2014-8, Grant no 302479/2019-8];Coordenação de Aperfeiçoamento de Pessoal de Nível Superior [Financing Code 001];Financiadora de Estudos e Projetos [Grant n 01.09.0447.00];Fundação de Amparo à Pesquisa do Estado de São Paulo [Grant no 2014/20344-9];