Studies of styrene, styrene oxide and 4-hydroxystyrene toxicity in CYP2F2 knockout and CYP2F1 humanized mice support lack of human relevance for mouse lung tumors

Regul Toxicol Pharmacol. 2013 Jun;66(1):24-9. doi: 10.1016/j.yrtph.2013.02.008. Epub 2013 Feb 27.


Styrene (S) is lung tumorigenic in mice but not in rats. S and its alkene-oxidized metabolite styrene oxide (SO) were not lung toxic in CYP2F2(-/-) [knockout] mice, indicating S-induced mouse lung tumors are mediated through mouse-specific CYP2F2-generated ring-oxidized metabolite(s) in lung bronchioles. The human relevance of the CYP2F MOA was assessed by insertion of a human CYP2F1, 2A13, 2B6 transgene into CYP2F2(-/-) mice; CYP2F1 expression and activity were confirmed in the transgenic (TG) mice. No evidence of cytotoxicity or increased cell proliferation (BrdU labeling) was seen in TG mice treated with either S or SO (200mg/kg/day ip for 5days). In contrast to S and SO, 4HS (105mg/kg/day ip for 5days) increased BrdU labeling 5-10-fold in WT mice, <3-fold increase in KO mice and 2-4-fold in TG mice. The limited response of 4HS in KO and TG mice may result from intrinsic toxicity or from further metabolism; regardless of the MOA, these findings indicate that the CYP2F-mediated tumorigenic MOA in WT mice is not operative for S, SO, or for 4HS putatively derived from metabolism of S by CYP2F1 in humans, and thus S-induced mouse lung tumors are unlikely to be relevant to human risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Cell Proliferation / drug effects
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Cytochrome P450 Family 2
  • Epoxy Compounds / toxicity*
  • Female
  • Humans
  • Lung Neoplasms / chemically induced
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Oxidoreductases, N-Demethylating / genetics
  • Phenols / toxicity*
  • Species Specificity
  • Styrene / toxicity*


  • Epoxy Compounds
  • Phenols
  • Styrene
  • Cytochrome P-450 Enzyme System
  • styrene oxide
  • Cyp2f2 protein, mouse
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A13 protein, human
  • CYP2B6 protein, human
  • CYP2F1 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P450 Family 2
  • Oxidoreductases, N-Demethylating
  • 4-vinylphenol