The toxicity of styrene to the nasal epithelium of mice and rats: studies on the mode of action and relevance to humans.
Inhaled styrene is known to be toxic to the nasal olfactory epithelium of both mice and rats, although mice are markedly more sensitive. In this study, the nasal tissues of mice exposed to 40 and 160 ppm styrene 6 h/day for 3 days had a number of degenerative changes including atrophy of the olfactory mucosa and loss of normal cellular organisation. Pretreatment of mice with 5-phenyl-1-pentyne, an inhibitor of both CYP2F2 and CYP2E1 completely prevented the development of a nasal lesion on exposure to styrene establishing that a metabolite of styrene, probably styrene oxide, is responsible for the observed nasal toxicity. Comparisons of the cytochrome P-450 mediated metabolism of styrene to its oxide, and subsequent metabolism of the oxide by epoxide hydrolases and glutathione S-transferases in nasal tissues in vitro, have provided an explanation for the increased sensitivity of the mouse to styrene. Whereas cytochrome P-450 metabolism of styrene is similar in rats and mice, the rat is able to metabolise styrene oxide at higher rates than the mouse thus rapidly detoxifying this electrophilic metabolite. Metabolism of styrene to its oxide could not be detected in human nasal tissues in vitro, but the same tissues did have epoxide hydrolase and glutathione S-transferase activities, and were able to metabolise styrene oxide efficiently, indicating that styrene is unlikely to be toxic to the human nasal epithelium.
Green
T
T
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ, Cheshire, UK. trevor.green@syngenta.com
Lee
R
R
Toghill
A
A
Meadowcroft
S
S
Lund
V
V
Foster
J
J
D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism; D009297:Nasal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020058:Styrene / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*
D000480:Alkynes; D001555:Benzene Derivatives; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D009153:Mutagens; C112922:5-phenyl-1-pentyne; D020058:Styrene; D003577:Cytochrome P-450 Enzyme System; C013690:styrene oxide; D019392:Cytochrome P-450 CYP2E1; C110333:Cyp2f2 protein, mouse; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases