Effect of methapyrilene hydrochloride on hepatic intracellular iron metabolism in vivo and in vitro

Toxicol Lett. 2017 Nov 5;281:65-73. doi: 10.1016/j.toxlet.2017.09.011. Epub 2017 Sep 19.


The liver, a central detoxification organ and main regulator of systemic iron homeostasis, is prone to damage by xenobiotics. In the present study, we investigated the effect of the hepatotoxicant and hepatocarcinogen methapyrilene hydrochloride on iron metabolism in rat liver in a repeat-dose in vivo toxicity study and in human HepaRG cells in vitro. Treatment of male Fischer 344 (F344) rats with methapyrilene at doses 40 and 80mg/kg body weight (bw)/day by gavage for 6 weeks resulted in changes in the expression of classic hepatotoxicity-related marker genes and iron homeostasis-related genes, especially a prominent, dose-dependent down-regulation of the transferrin (Tf) gene and an up-regulation of the ferritin, light chain (Ftl) gene. A decrease in the level of TF and an increase in the level of FTL also occurred in methapyrilene-treated differentiated HepaRG cells, indicating the existence of interspecies and in vitro-in vivo similarities in the disturbance of cellular iron homeostasis upon liver injury. In contrast, there was minimal overlap in the expression of liver toxicity-marker genes in the livers of rats and in HepaRG cells treated with methapyrilene. Importantly, the decrease of transferrin at mRNA and protein levels occurred after the treatment with a low dose of methapyrilene that exhibited minimal cytotoxicity. These results demonstrate the significance of the dysregulation of hepatic iron metabolism in the pathogenesis and mechanism of chemical-induced liver toxicity and suggest that these changes may be sensitive and useful indicators of potentially hepatotoxic chemicals.

Keywords: Ferritin; Hepatotoxicity; Iron metabolism; Methapyrilene; Transferrin.

MeSH terms

  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Ferritins / genetics
  • Ferritins / metabolism
  • Genetic Markers
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Iron / metabolism*
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Methapyrilene / toxicity*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred F344
  • Transferrin / genetics
  • Transferrin / metabolism
  • Up-Regulation


  • Genetic Markers
  • RNA, Messenger
  • Transferrin
  • Ferritins
  • Methapyrilene
  • Iron