Noncompetitive mixed-type inhibition of rainbow trout CYP1A catalytic activity by clotrimazole.
Over the past two decades a number of antifungal imidazole derivatives have been approved for use in agricultural. The purpose of this study was to characterize the interaction of a model antifungal imidazole compound with a cytochrome P450 isozyme in a species of fish. Clotrimazole inhibited rainbow trout (Oncorhyncus mykiss) hepatic CYP1A-catalyzed ethoxyresorufin O-deethylase (EROD) activity in vivo and in vitro. Although clotrimazole inhibited EROD activity in vivo, it did not effect CYP1A mRNA levels. Addition of clotrimazole to microsomes produced a type II binding spectrum and clotrimazole was determined to be a noncompetitive mixed-type inhibitor of EROD activity with an IC50 of 190 nM. Since antifungal imidazole compounds may be co-applied with other pesticides, inhibition of cytochrome P450 activity by antifungal imidazole compounds may lead to unexpected toxicological interactions.
Levine
S L
SL
Center for Environmental Toxicology and Statistics, Department of Zoology, Miami University, Oxford, OH 45056, USA. SLL13@psu.edu
Oris
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JT
D000818:Animals; D003022:Clotrimazole / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D017686:Oncorhynchus mykiss / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013053:Spectrophotometry
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1; D003022:Clotrimazole