Effects of eleven isothiocyanates on P450 2A6- and 2A13-catalyzed coumarin 7-hydroxylation.
Many isothiocyanates (ITCs), both naturally occurring and synthetic, are potent and selective inhibitors of carcinogenesis in animal models and are now viewed as a class of promising chemopreventive agents. We have investigated the ability of 11 ITCs to inhibit and/or inactivate P450 2A6- and 2A13-mediated coumarin 7-hydroxylation. Two of these 11 ITCs, phenylpropyl isothiocyanate (PPITC) and phenylhexyl isothiocyanate (PHITC), were potent inhibitors of P450 2A13. The K I values for the inhibition of P450 2A13-mediated coumarin 7-hydroxylation by PPITC and PHITC were approximately 0.14 and 1.1 microM, respectively. P450 2A6 was also inhibited by these two ITCs; however, the K I values indicated they were approximately 10-20-fold less potent for P450 2A6 than for P450 2A13. Most of the ITCs tested, including PPITC and PHITC, showed some degree of inactivation of both P450s; however, only one compound, tert-butyl isothiocyanate (tBITC), showed significant inactivation of P450 2A13 at a concentration of 10 microM. None of the ITCs caused significant inactivation of P450 2A6 at this concentration. tBITC inactivated P450 2A13 with an apparent K I of 4.3 microM and a k inact of 0.94 min (-1). Inactivation of P450 2A6 by tBITC was observed only at high concentrations and long incubation times. The observed differences in inhibition and/or inactivation of P450 2A6 and 2A13 by a few of the isothiocyanates suggest that these compounds may be useful for structure-function studies.
von Weymarn
Linda B
LB
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
Chun
Jamie A
JA
Knudsen
Gabriel A
GA
Hollenberg
Paul F
PF
D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D003198:Computer Simulation; D003374:Coumarins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D065637:Cytochrome P-450 CYP2A6; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D007093:Imidazoles / Q000737:chemistry*; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure
D003374:Coumarins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D017879:Isothiocyanates; C517283:coumarin 7; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; D065637:Cytochrome P-450 CYP2A6