Analysis of the cytotoxic, genotoxic, mutagenic, and pro-oxidant effect of synephrine, a component of thermogenic supplements, in human hepatic cells in vitro

Toxicology. 2019 Jun 15;422:25-34. doi: 10.1016/j.tox.2019.04.010. Epub 2019 Apr 17.


Thermogenic supplements containing synephrine (SN) are widely used to weight loss. SN is a proto-alkaloid naturally found in the bark of immature fruits of Citrus aurantium (bitter orange) that has been added to thermogenic supplements due to its chemical and pharmacological similarity with adrenergic amines, such as ephedrine and amphetamines. Although orally ingested SN is mainly metabolized in the liver, it remains unclear whether it affects the redox status and genetic material of human hepatic cells. The present study aims to examine whether SN affects cell viability, cell cycle, redox balance, genomic stability, and expression of the DNA damage response (DDR)-related genes ATM, ATR, CHEK1, CHECK2, TP53, and SIRT1 in HepG2 cells - used as in vitro hepatocyte model. SN induced overproduction of intracellular reactive oxygen species (ROS) after 6 h of treatment with the three concentrations tested (2, 20 and 200 μM). After 24 h of treatment, SN at 200 μM induced intracellular ROS overproduction and exerted cytostatic effects, while SN at 20 and 200 μM increased the levels of GPx and GSH. SN was not cytotoxic (2-5000 μM), genotoxic, and mutagenic and did not alter the expression of DDR-related genes (2-200 μM), indicating that the fast/specific SN metabolization and upregulation of antioxidant defense components to detoxify intracellular ROS were sufficient to prevent intracellular damage in HepG2 cells. In conclusion, SN showed no cytotoxic, genotoxic, and mutagenic potential at relevant concentrations for thermogenic users in human hepatic cells in vitro, although, it plays pro-oxidative action, and cytostatic effects. Taken together, our results suggest that other investigations about the hazard absence of this thermogenic compound should be performed.

Keywords: DNA damage; Gene expression; Micronucleus assay; Oxidative stress; Toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / drug effects
  • Cell Survival / drug effects
  • Comet Assay
  • Cytotoxins / toxicity*
  • Dietary Supplements / adverse effects*
  • Gene Expression / drug effects
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Oxidants / toxicity*
  • Reactive Oxygen Species / metabolism
  • Synephrine / toxicity*


  • Cytotoxins
  • Oxidants
  • Reactive Oxygen Species
  • Synephrine