![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 30, Issue 5, 483-487, May 2002
The Miami Valley Laboratories, Coumarin, a widely used fragrance ingredient, is a rat liver and
mouse lung toxicant. Species differences in toxicity are metabolism-dependent, with injury resulting from the cytochrome P450-mediated formation of coumarin 3,4-epoxide (CE). In this study,
the enzymes responsible for coumarin activation in liver and lung were
determined. Recombinant human and rat CYP1A forms and recombinant human
CYP2E1 readily catalyzed CE production. Coinhibition with CYP1A1/2 and
CYP2E1 antibodies blocked CE formation by 38, 84, and 67 to 92%
(n = 3 individual samples) in mouse, rat, and human
hepatic microsomes, respectively. Although CYP1A and 2E forms seem to
be the most active catalysts of CE formation in liver, studies
conducted with the mechanism-based inhibitor 5-phenyl-pentyne
demonstrated that CYP2F2 is responsible for up to 67% of CE formation
in whole mouse lung microsomes. In contrast to the CE pathway, coumarin
3-hydroxylation is a minor product of coumarin in liver microsomes from
mice, rats, and humans and is catalyzed predominately by CYP3A and
CYP1A forms, confirming that CE and 3-hydroxycoumarin are formed via
distinct metabolic pathways.
Procter & Gamble, Cincinnati,
Ohio
This article has been cited by other articles:
|
|
 |
|
  B. J. Davies, J. K. Coller, A. A. Somogyi, R. W. Milne, and B. C. Sallustio CYP2B6, CYP2D6, and CYP3A4 Catalyze the Primary Oxidative Metabolism of Perhexiline Enantiomers by Human Liver Microsomes Drug Metab. Dispos., January 1, 2007; 35(1): 128 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Jeffrey, M. J. Iatropoulos, and G. M. Williams Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals Toxicol Pathol, December 1, 2006; 34(7): 827 - 852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Kienhuis, H. M. Wortelboer, J.-C. Hoflack, E. J. Moonen, J. C.S. Kleinjans, B. van Ommen, J. H. M. van Delft, and R. H. Stierum Comparison of Coumarin-Induced Toxicity between Sandwich-Cultured Primary Rat Hepatocytes and Rats in Vivo: A Toxicogenomics Approach Drug Metab. Dispos., December 1, 2006; 34(12): 2083 - 2090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Yun, K.-H. Kim, M. W. Calcutt, and F. P. Guengerich Kinetic Analysis of Oxidation of Coumarins by Human Cytochrome P450 2A6 J. Biol. Chem., April 1, 2005; 280(13): 12279 - 12291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Vassallo, S. M. Hicks, S. L. Born, and G. P. Daston Roles for Epoxidation and Detoxification of Coumarin in Determining Species Differences in Clara Cell Toxicity Toxicol. Sci., November 1, 2004; 82(1): 26 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Vassallo, S. M. Hicks, G. P. Daston, and L. D. Lehman-McKeeman Metabolic Detoxification Determines Species Differences in Coumarin-Induced Hepatotoxicity Toxicol. Sci., August 1, 2004; 80(2): 249 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. H. Mitchell, C. E. Rogge, T. Gierahn, and B. G. Fox Bioinorganic Chemistry Special Feature: Insight into the mechanism of aromatic hydroxylation by toluene 4-monooxygenase by use of specifically deuterated toluene and p-xylene PNAS, April 1, 2003; 100(7): 3784 - 3789. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
