Effect of interleukin (IL)-8 on benzo[a]pyrene metabolism and DNA damage in human lung epithelial cells

Toxicology. 2017 Apr 15;381:64-74. doi: 10.1016/j.tox.2017.02.013. Epub 2017 Feb 24.

Abstract

It has been well established that inflammation and concurrent mutagenic exposures drive the carcinogenic process in a synergistic way. To elucidate the role of the inflammatory cytokine IL-8 in this process, we studied its effect on the activation and deactivation of the chemical mutagen benzo[a]pyrene B[a]P in the immortalized pulmonary BEAS-2B cell line. After 24h incubation with B[a]P in the presence or absence of IL-8, the B[a]P induced cytochrome P450 1A1 and 1B1 (CYP1A1 and CYP1B1) gene expression and CYP1A1 enzyme activity was significantly higher in the presence of the cytokine. Consistent with these findings, we observed higher concentration of the metabolite B[a]P-7,8-diol under concurrent IL-8 treatment conditions. Interestingly, we also found higher concentrations of unmetabolized B[a]P. To explain this, we examined the downstream effects of IL-8 on NADPH oxidases (NOXes). IL-8 lowered the intracellular NADPH level, but this effect could not explain the changes in B[a]P metabolism. IL-8 also significantly depleted intracellular glutathione (GSH), which also resulted in enhanced levels of unmetabolized B[a]P, but increased concentrations of the metabolite B[a]P-7,8-diol. No differences in B[a]P-DNA adducts level were found between B[a]P and B[a]P combined with IL-8, and this might be due to a 3-fold increase in nucleotide excision repair (NER) after IL-8 treatment. These findings suggest that IL-8 increased the formation of B[a]P-7,8-diol despite an overall delayed B[a]P metabolism via depletion of GSH, but DNA damage levels were unaffected due to an increase in NER capacity.

Keywords: Benzo[a]pyrene (B[a]P); DNA adducts; Glutathione (GSH); Interleukin (IL)-8; NADPH oxidase pathway (NOX); NADPH-dependent cytochrome P450s 1A1/1B1 (CYP1A1/CYP1B1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzo(a)pyrene / toxicity*
  • Carcinogens / toxicity
  • Cell Line
  • Cell Survival / drug effects
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1A1 / metabolism
  • Cytochrome P-450 CYP1B1 / genetics
  • Cytochrome P-450 CYP1B1 / metabolism
  • DNA Damage / drug effects*
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Humans
  • Interleukin-8 / pharmacology*
  • Lung / cytology
  • NADP / metabolism
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Carcinogens
  • Interleukin-8
  • RNA, Messenger
  • Benzo(a)pyrene
  • NADP
  • CYP1A1 protein, human
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1B1
  • NADPH Oxidases