Benzo[a]pyrene treatment modulates Nrf2/Keap1 axis and changes the metabolic profile in rat lung cancer

Chem Biol Interact. 2023 Mar 1:373:110373. doi: 10.1016/j.cbi.2023.110373. Epub 2023 Feb 1.


Lung cancer is an aggressive malignancy and the leading cause of cancer-related deaths. Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon, plays a pivotal role in lung carcinogenesis. Uncovering the molecular mechanism underlying the pathophysiology of B[a]P induced malignancy is crucial. Male Sprague Dawley rats were induced with B[a]P to generate a lung cancer model. The B[a]P administered rats show increased body and lung weight, loss of normal pulmonary architecture, and decreased survival. This study demonstrated that B[a]P upregulates activating transcription factor-6 (ATF6) and C/EBP Homologous Protein (CHOP) and induces endoplasmic reticulum (ER) stress. B[a]P also dysregulated mitochondrial homeostasis by upregulating, PTEN-induced putative kinase-1 (PINK1) and Parkin. B[a]P affected the levels of superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA), and increased oxidative stress. B[a]P exposure downregulated Kelch-like ECH-associated protein 1 (Keap1) and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase-1(HO1). The metabolomic study identified that biosynthesis of nucleotide, amino acids, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), and glutathione metabolism were up-accumulated. On the other hand, lower accumulation of fatty acids e.g., palmitic acid, stearic acid, and oleic acid were reported in the B[a]P induced group. Overall, the results of this study indicate that B[a]P treatment affects several signaling and metabolic pathways, whose dysregulation might be involved in lung cancer induction.

Keywords: Benzo[a]pyrene; Endoplasmic reticulum stress; Lung cancer; Metabolomics; Mitochondrial dysfunction; Oxidative stress.

MeSH terms

  • Animals
  • Benzo(a)pyrene
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Lung Neoplasms*
  • Male
  • Metabolome
  • NF-E2-Related Factor 2* / metabolism
  • Oxidative Stress
  • Rats
  • Rats, Sprague-Dawley


  • Benzo(a)pyrene
  • KEAP1 protein, rat
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2