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.