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Xenobiotica
the fate of foreign compounds in biological systems
Volume 36, 2006 - Issue 9
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Metabolism of myclobutanil and triadimefon by human and rat cytochrome P450 enzymes and liver microsomes

H. A. Barton National Center for Computational Toxicology, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USACorrespondence[email protected]
,
J. Tang Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
H. A. Barton National Center for Computational Toxicology, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USACorrespondence[email protected]
,
J. Tang Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
Y. M. Sey National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
J. P. Stanko Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
R. N. Murrell National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA; Department of Environmental and Molecular Toxicology, NC State University, Raleigh, NC, USA
,
H. A. Barton National Center for Computational Toxicology, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USACorrespondence[email protected]
,
J. Tang Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
Y. M. Sey National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
J. P. Stanko Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
R. N. Murrell National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA; Department of Environmental and Molecular Toxicology, NC State University, Raleigh, NC, USA
,
J. C. Rockett National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
H. A. Barton National Center for Computational Toxicology, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USACorrespondence[email protected]
,
J. Tang Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
Y. M. Sey National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
J. P. Stanko Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
,
R. N. Murrell National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA; Department of Environmental and Molecular Toxicology, NC State University, Raleigh, NC, USA
,
J. C. Rockett National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
&
D. J. Dix National Center for Computational Toxicology, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA
 show all
Pages 793-806 | Received 04 Apr 2006, Accepted 23 May 2006, Published online: 11 Aug 2009
 
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Abstract

Metabolism of two triazole-containing antifungal azoles was studied using expressed human and rat cytochrome P450s (CYP) and liver microsomes. Substrate depletion methods were used due to the complex array of metabolites produced from myclobutanil and triadimefon. Myclobutanil was metabolized more rapidly than triadimefon, which is consistent with metabolism of the n-butyl side-chain in the former and the t-butyl group in the latter compound. Human and rat CYP2C and CYP3A enzymes were the most active. Metabolism was similar in microsomes prepared from livers of control and low-dose rats. High-dose (115 mg kg−1 day−1 of triadimefon or 150 mg kg−1 day−1 of myclobutanil) rats showed increased liver weight, induction of total CYP, and increased metabolism of the two triazoles, though the apparent Km appeared unchanged relative to the control. These data identify CYP enzymes important for the metabolization of these two triazoles. Estimated hepatic clearances suggest that CYP induction may have limited impact in vivo.

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