Synergistic and antagonistic interactions of binary mixtures of polycyclic aromatic hydrocarbons in the upregulation of CYP1 activity and mRNA levels in precision-cut rat liver slices

Environ Toxicol. 2017 Mar;32(3):764-775. doi: 10.1002/tox.22276. Epub 2016 Apr 20.


The current studies investigate whether synergistic or antagonistic interactions in the upregulation of CYP1 activity occur in binary mixtures of polycyclic aromatic hydrocarbons (PAHs) involving benzo[a]pyrene and five other structurally diverse PAHs of varying carcinogenic activity. Precision-cut rat liver slices were incubated with benzo[a]pyrene alone or in combination with a range of concentrations of a second PAH, and ethoxyresorufin O-deethylase, CYP1A1 and CYP1B1 mRNA levels determined. Concurrent incubation of benzo[a]pyrene with either dibenzo[a,h]anthracene or fluoranthene in liver slices led to a synergistic interaction, at least at low concentrations, in that ethoxyresorufin O-deethylase activity was statistically higher than the added effects when the slices were incubated with the individual compounds. In contrast, benzo[b]fluoranthene and, at high doses only, dibenzo[a,l]pyrene gave rise to antagonism, whereas 1-methylphenanthrene had no effect at all concentrations studied. When CYP1A1 mRNA levels were monitored, benzo[b]fluoranthene gave rise to an antagonistic response when incubated with benzo[a]pyrene, whereas all other compounds displayed synergism, with 1-methylphenathrene being the least effective. A similar picture emerged when CYP1B1 mRNA levels were determined, though the effects were less pronounced. In conclusion, it has been demonstrated that the benzo[a]pyrene-mediated upregulation of CYP1, at the mRNA and activity levels, is synergistically and antagonistically modulated by other PAHs. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 764-775, 2017.

Keywords: cytochrome P450; interactions; polycyclic aromatic hydrocarbons; precision-cut tissue slices; risk assessment.

MeSH terms

  • Animals
  • Benz(a)Anthracenes / toxicity
  • Benzo(a)pyrene / toxicity
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1A1 / metabolism*
  • Cytochrome P-450 CYP1B1 / metabolism*
  • Drug Synergism
  • In Vitro Techniques
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Polycyclic Aromatic Hydrocarbons / toxicity*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Up-Regulation / drug effects*


  • Benz(a)Anthracenes
  • Polycyclic Aromatic Hydrocarbons
  • RNA, Messenger
  • Benzo(a)pyrene
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1B1
  • 1,2,5,6-dibenzanthracene