Toxicological Sciences, Vol 51, 195-201, Copyright © 1999 by Society of Toxicology
DE Hynes, DB DeNicola and GP Carlson
Styrene is pneumotoxic in mice. It is metabolized by pulmonary microsomes
of both mouse and rat to styrene oxide (SO), presumed to be the toxic
metabolite of styrene, and known to be genotoxic. To determine which
pulmonary cell types are responsible for styrene metabolism, and which
cytochromes P450 are associated with the bioactivation of styrene, we
isolated enriched fractions of mouse and rat Clara and type II cells in
order to determine the rate of styrene metabolism, with and without
chemical inhibitors. Mouse Clara cells readily metabolized styrene to SO.
Diethyldithiocarbamate, a CYP2E1 inhibitor, caused less inhibition of SO
formation in Clara cells isolated from mice than previously found with
pulmonary microsomes. As in microsomes, 5-phenyl-1-pentyne, a CYP2F2
inhibitor, inhibited the formation of both enantiomers.
alpha-Naphthoflavone, a CYP1A inhibitor, did not inhibit SO formation in
Clara cells. alpha- Methylbenzylaminobenzotriazole, a CYP2B inhibitor,
exhibited minimal inhibition of SO production at 10 microM and less at 1
microM. The microsomal and isolated cell studies indicate that CYP2E1 and
CYP2F2 are the primary cytochromes P450 involved in pulmonary styrene
metabolism. Styrene metabolizing activity was much greater in Clara cells
than in type II pneumocytes, which demonstrated essentially no activity.
Styrene-metabolizing activity was several-fold higher in the mouse than in
rat Clara cells. The more pneumotoxic and genotoxic form, R-SO, was
preferentially formed in mice, and S-SO was preferentially formed in rats.
These findings indicate the importance of Clara cells in styrene metabolism
and suggest that differences in metabolism may be responsible for the
greater susceptibility of the mouse to styrene- induced toxicity.
ARTICLES
Metabolism of styrene by mouse and rat isolated lung cells
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.
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