Studies on trans-cinnamaldehyde II: Mechanisms of cytotoxicity in rat isolated hepatocytes

Toxicology in Vitro : an International Journal Published in Association with BIBRA
N J Swales, J Caldwell

Abstract

The mechanism of cinnamaldehyde (CA) cytotoxicity has been investigated in isolated F344 rat hepatocytes. CA reacts spontaneously with reduced glutathione (GSH) in the test-tube. In contrast, cinnamic acid (CAC) and cinnamyl alcohol (CALC) do not react with GSH. CA is the reactive cinnamyl species, since this compound is the most potent intracellular GSH depletor and exhibits the highest cytotoxicity in hepatocyte suspensions. The dose-response curve for CA is very steep, with a threshold cytotoxic concentration of 10(-3)m. CALC is equipotent with CA in depleting GSH but exhibits a latency in this effect, consistent with CALC being metabolized to CA in order to deplete GSH. CAC had no effect on GSH and was non-cytotoxic. Predepletion of GSH with diethyl maleate and/or inhibition of gamma-glutamylcysteine synthetase by l-buthionine S,R-sulfoximine reduces the threshold concentration for cytotoxicity. Inhibition of oxidation of CA to CAC (the major route of metabolism) with cyanamide also increases both CA cytotoxicity and GSH depletion. Ethanol increases GSH depletion by CA without inducing cytotoxicity, but has no further effect on the GSH depletion or cytotoxicity in cyanamide and CA-treated suspensions.

References

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Citations

Nov 14, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Joep BrinkmannAndreas Luch
Feb 7, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jeannine ChanJohn P Harrelson
Apr 7, 2005·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·C S LetiziaA M Api
Apr 7, 2005·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·J CocchiaraA M Api
Apr 7, 2005·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·C S LetiziaA M Api
Sep 28, 2010·Toxicology and Applied Pharmacology·Stephanie M MartinezIvan Rusyn
Aug 12, 2014·SAR and QSAR in Environmental Research·S B Gunturi, N Ramamurthi

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