CYP4F2 repression and a modified alpha-tocopherol (vitamin E) metabolism are two independent consequences of ethanol toxicity in human hepatocytes

Toxicol In Vitro. 2017 Apr;40:124-133. doi: 10.1016/j.tiv.2016.12.014. Epub 2017 Jan 3.

Abstract

The expression of CYP4F2, a form of cytochrome P-450 with proposed role in α-tocopherol and long-chain fatty acid metabolism, was explored in HepG2 and HepaRG human hepatocytes during ethanol toxicity. Cytotoxicity, ROS production, and JNK and ERK1/2 kinase signaling increased in a dose and time-dependent manner during ethanol treatments; CYP4F2 gene expression decreased, while other CYP4F forms, namely 4F11 and 12, increased along with 3A4 and 2E1 isoforms. α-Tocopherol antagonized the cytotoxicity and CYP4F2 gene repression effect of ethanol in HepG2 cells. Ethanol stimulated the tocopherol-ω-hydroxylase activity and the other steps of vitamin E metabolism, which points to a minor role of CYP4F2 in this metabolism of human hepatocytes. PPAR-γ and SREBP-1c followed the same expression pattern of CYP4F2 in response to ethanol and α-tocopherol treatments. Moreover, the pharmacological inhibition of PPAR-γ synergized with ethanol in decreasing CYP4F2 protein expression, which suggests a role of this nuclear receptor in CYP4F2 transcriptional regulation. In conclusion, ethanol toxicity modifies the CYP expression pattern of human hepatic cells impairing CYP4F2 transcription and protein expression. These changes were associated with a lowered expression of the fatty acid biosynthesis regulators PPAR-γ and SREBP-1c, and with an increased enzymatic catabolism of vitamin E. CYP4F2 gene repression and a sustained vitamin E metabolism appear to be independent effects of ethanol toxicity in human hepatocytes.

Keywords: Alcohol liver disease; CYP4F2; Ethanol; PPAR-γ; SREBP-1; α-Tocopherol.

MeSH terms

  • Antioxidants / metabolism*
  • Cell Line
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytochrome P-450 Enzyme Inhibitors / toxicity*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Ethanol / toxicity*
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • PPAR gamma / metabolism
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • alpha-Tocopherol / metabolism*

Substances

  • Antioxidants
  • Cytochrome P-450 Enzyme Inhibitors
  • PPAR gamma
  • RNA, Messenger
  • Reactive Oxygen Species
  • Sterol Regulatory Element Binding Protein 1
  • Ethanol
  • Cytochrome P-450 Enzyme System
  • alpha-Tocopherol