Metabolism of myclobutanil and triadimefon by human and rat cytochrome P450 enzymes and liver microsomes.
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.
Barton
H A
HA
National Center for Computational Toxicology, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. habarton@alum.mit.edu
Tang
J
J
Sey
Y M
YM
Stanko
J P
JP
Murrell
R N
RN
Rockett
J C
JC
Dix
D J
DJ
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D005260:Female; D005659:Fungicides, Industrial / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D005659:Fungicides, Industrial; D007527:Isoenzymes; D009570:Nitriles; D014230:Triazoles; C032910:triadimefon; C446685:systhane; D019362:Cytochrome P-450 CYP2B1