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Vol. 288, Issue 2, 463-471, February 1999
Wadsworth Center, Coumarin was previously found to cause tissue-selective toxicity in the
olfactory mucosa (OM) of rats and mice, with rats being the more
sensitive species. The aim of this study was to explore the role of
target tissue biotransformation in OM-selective toxicity and the
metabolic basis of the species differences in coumarin toxicity. At
least six coumarin metabolites were detected in OM microsomal
reactions, with o-hydroxyphenylacetaldehyde
(o-HPA) being the most abundant. Formation of
o-HPA was inhibited by reduced glutathione, confirming
its origin from a reactive intermediate. There were significant
differences in the rates and metabolite profiles of coumarin metabolism
in the livers of Wistar rats and C57BL/6 mice. The rates of metabolic
activation of coumarin, as indicated by the formation of
o-HPA, were comparable in OM microsomes of the two
species but about 25- and 3-fold higher in OM than in liver microsomes
of rats and mice, respectively. Thus, target tissue activation seems to
play an important role in the tissue-selective toxicity, whereas
differences in the rates of hepatic metabolism may be responsible for
the species difference in olfactory toxicity. Purified, heterologously
expressed mouse CYP2A5 and CYP2G1 produced 7-hydroxycoumarin and
o-HPA as the predominant products, respectively. Kinetic
analysis and immunoinhibition studies indicated that the OM-specific
CYP2G1 plays the major role in metabolic activation of coumarin.
Furthermore, of 13 human cytochrome P-450s (P-450s) examined, five
(CYP1A1, CYP1A2, CYP2B6, CYP2E1, and CYP3A4) were active in the
metabolic activation of coumarin, suggesting a potential risk of
coumarin toxicity in humans.
0022-3565/99/2882-0463$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
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