Analysis of medaka cytochrome P450 3A homotropic and heterotropic cooperativity.
We have previously demonstrated that medaka CYP3A is associated with metabolism of several endobiotics including steroids and bile acids. In this study, we demonstrate that medaka CYP3A catalysis exhibits unusual kinetic behaviors consistent with allosteric interaction which cannot be described by hyperbolic kinetic models. Using 7-benzyloxy-4-(trifluoromethyl)-coumarin (BFC) and nonylphenol as CYP3A substrates, we describe both homotropic and heterotropic cooperative interactions. Given the role of CYP3A in maintaining the homeostatic balance for numerous endobiotics, enzymatic activation/inhibition by endocrine disruptors (EDCs) represents a putative (non-genomic) mechanism for endocrine disruption.
Kullman
Seth W
SW
Nicholas School of the Environment and Earth Sciences, Duke University, Box 90328, Durham, NC 27708, USA. swkull@duke.edu
Kashiwada
Shosaku
S
Hinton
David E
DE
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002384:Catalysis; D003374:Coumarins / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D005453:Fluorescence; D007700:Kinetics; D008956:Models, Chemical; D009990:Oryzias / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism; D011485:Protein Binding; D013379:Substrate Specificity
C419147:7-benzyloxy-4-trifluoromethylcoumarin; D003374:Coumarins; D010636:Phenols; C025256:nonylphenol; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating