Different modes of inhibition of mouse Cyp2a5 and rat CYP2A3 by the food-derived 8-methoxypsoralen.
CYP2A enzymes are responsible for nicotine metabolism and for activating tobacco-related carcinogens. Inhibition of CYP2A is a promising approach in chemoprevention, which could lead to a decrease in cigarette consumption and to a reduction in tobacco-related cancer risk. 8-Methoxypsoralen (8-MOP) is a mechanism-based inhibitor of human CYP2A6 and CYP2A13. 8-MOP is also an inhibitor of Cyp2a5, but the mode of this inhibition is unknown. There is no published data on the inhibition of CYP2A3 by 8-MOP. The objective of this work was to investigate the characteristics of 8-MOP inhibition on mouse hepatic Cyp2a5 and rat nasal CYP2A3, in order to determine the best experimental model for chemoprevention studies using 8-MOP. The results show that 8-MOP inhibits CYP2a5 through three different mechanisms: competitive, non-competitive (K(iu)=1.7 microM), and mechanism-based (K(inactivation) of 0.17 min(-1)). By contrast, 8-MOP was able to inhibit CYP2A3-mediated coumarin 7-hydroxylase only in a non-competitive way (K(iu)=0.22 microM). In conclusion, we showed that 8-MOP inhibits Cyp2a5 and CYP2A3 through different mechanisms.
Visoni
S
S
Laboratório de Toxicologia e Biologia Molecular, Departamento de Bioquímica, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Meireles
N
N
Monteiro
L
L
Rossini
A
A
Pinto
L F R
LF
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D006899:Mixed Function Oxygenases; C585519:Cyp2a3 protein, rat; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D008730:Methoxsalen