title: 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.
abstract: 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.
authors: ToxWorks, Bridgeton, NJ 08302, USA. toxworks@aol.com
authors: G
authors: G
authors: Cruzan
authors: J
authors: J
authors: Bus
authors: J
authors: J
authors: Hotchkiss
authors: R
authors: R
authors: Sura
authors: C
authors: C
authors: Moore
authors: G
authors: G
authors: Yost
authors: M
authors: M
authors: Banton
authors: S
authors: S
authors: Sarang
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004852:Epoxy Compounds / Q000633:toxicity*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010636:Phenols / Q000633:toxicity*; D013045:Species Specificity; D020058:Styrene / Q000633:toxicity*
chemical_list: D004852:Epoxy Compounds; D010636:Phenols; D020058:Styrene; D003577:Cytochrome P-450 Enzyme System; C013690:styrene oxide; C110333:Cyp2f2 protein, mouse; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; C585599:CYP2B6 protein, human; C110332:CYP2F1 protein, human; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; D010089:Oxidoreductases, N-Demethylating; C030626:4-vinylphenol