Toxicological Sciences, Vol 51, 300-309, Copyright © 1999 by Society of Toxicology
SL Born, AS Fix, D Caudill and LD Lehman-McKeeman
Coumarin was identified as a mouse-lung carcinogen following oral gavage
administration in a chronic bioassay, and was shown to cause the selective
necrosis of terminal bronchiolar Clara (non-ciliated bronchiolar
epithelial) cells in the mouse lung after acute administration. After oral
gavage, a similar effect was not observed in the terminal bronchioles of
rats, suggesting that coumarin-mediated Clara cell toxicity is a
species-specific effect. Using coumarin dosages (50 and 200 mg/kg) and a
dosing schedule modeled after the chronic bioassay, the current study
examined the effects of repeated coumarin administration in mouse lung. A
single dosage of coumarin (200 mg/kg) caused swelling of Clara cells and
necrosis in mouse-lung terminal bronchioles. However, after 5 consecutive
oral doses of coumarin (200 mg/kg), the mouse lung became tolerant to
coumarin, and although areas of bronchiolar epithelial flattening and
hyperplasia were noted, Clara cell necrosis was not observed. After 10
doses of coumarin, mouse lungs appeared nearly normal. Coumarin-mediated
Clara cell injury is thought to result from the cytochrome P450-catalyzed
formation of coumarin 3,4-epoxide and Western analysis of whole mouse lung
microsomal P450 content indicated that, commensurate with Clara cell
necrosis, many P450s were decreased. However, P450 levels appeared
qualitatively normal in lung microsomes from tolerant mice. Similarly,
coumarin epoxidation and 7-hydroxylation rates in whole lung microsomes
from tolerant animals were similar to controls. To determine if animals
tolerant to coumarin were tolerant to other Clara cell toxicants, a single
toxic dose of naphthalene (200 mg/kg) was administered to coumarin-tolerant
mice. Coumarin pretreatment reduced naphthalene- mediated Clara cell
toxicity, supporting the hypothesis that tolerance may result from general
biochemical and molecular changes and not exclusively from alterations in
chemical metabolism.
ARTICLES
Development of tolerance to Clara cell necrosis with repeat administration of coumarin
Procter and Gamble Company, Miami Valley Laboratories, Cincinnati, Ohio 45253, USA. born.sl@pg.com
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