Apo-8'-lycopenal induces expression of HO-1 and NQO-1 via the ERK/p38-Nrf2-ARE pathway in human HepG2 cells

J Agric Food Chem. 2012 Feb 15;60(6):1576-85. doi: 10.1021/jf204451n. Epub 2012 Feb 1.


Lycopene and its metabolite apo-10'-lycopenoic acid have been shown to induce phase II detoxifying/antioxidant enzymes through activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2)-antioxidant response element (ARE) transcription system. However, little is known about whether apo-8'-lyocpenal, one of the main metabolites of lycopene in rat livers, in lycopene-containing food, and in human plasma, has similar effects. This study investigated the effect of apo-8'-lycopenal on Nrf2-ARE system-mediated heme oxygenase 1 (HO-1) and NAD(P)H:quinine oxidoreductase 1 (NQO-1) expression in human HepG2 cells. It was found that apo-8'-lycopenal (1-10 μM) significantly increased nuclear Nrf2 accumulation, ARE-luciferase activity, Nrf2-ARE binding activity, chymotrypsin-like activity, and downstream HO-1 and NQO-1 expression, but decreased cytosolic Kelch-like ECH-associated protein 1 (Keap1) expression. Results also revealed that the ERK/p38-Nrf2 pathway is involved in activation of HO-1 and NQO-1 expression by apo-8'-lycopenal using Nrf2 siRNA and ERK/p38 specific inhibitors. In addition, the activation time of lycopene on nuclear Nrf2 accumulation is slower than that of apo-8'-lycopenal, suggesting that the chemopreventive effects of lycopene may be partially attributed to its metabolites.

MeSH terms

  • Anticarcinogenic Agents
  • Antioxidants / pharmacology
  • Carotenoids / pharmacology*
  • Fatty Acids, Unsaturated / pharmacology*
  • Gene Expression / drug effects*
  • Heme Oxygenase-1 / genetics*
  • Hep G2 Cells
  • Humans
  • Lycopene
  • MAP Kinase Signaling System / drug effects*
  • NAD(P)H Dehydrogenase (Quinone) / genetics*
  • NF-E2-Related Factor 2 / metabolism*
  • Response Elements / drug effects
  • Signal Transduction / drug effects*


  • Anticarcinogenic Agents
  • Antioxidants
  • Fatty Acids, Unsaturated
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • apo-10'-lycopenoic acid
  • apo-8'-lycopenal
  • Carotenoids
  • Heme Oxygenase-1
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Lycopene