In vitro inhibition of cytochrome P450 enzymes in human liver microsomes by a potent CYP2A6 inhibitor, trans-2-phenylcyclopropylamine (tranylcypromine), and its nonamine analog, cyclopropylbenzene

Currently, there are no selective, well characterized inhibitors for CYP2A6 . Therefore, the effects of trans-(+/-)-2-phenylcyclopropylamine (tranylcyp romine), a potent CYP2A6 inhibitor, on human liver microsomal cytochromes P 450 (CYP) were studied to elucidate its selectivity. The IC50 value of tran ylcypromine in coumarin 7-hydroxylation (CYP2A6 model activity) was 0.42 +/ - 0.07 muM and in chlorzoxazone 6-hydroxylation (CYP2E1 model activity) 3.0 +/- 1.1 mM. The IC50 values for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A 4 activities were >10 muM. Potency and selectivity of tranylcypromine were strongly dependent on the amine group, because its nonamine analog cyclopro pylbenzene was much less potent inhibitor of CYP1A, CYP2A6, CYP2C19, and CY P2E1 activities and did not inhibit at all CYP2C9, CYP2D6, or CYP3A4 activi ties. In human liver microsomes tranylcypromine induced type II and cyclopr opylbenzene type I difference spectrum. According to the double reciprocal analysis of these spectral responses both tranylcypromine and cyclopropylbe nzene may have at least two P450-related binding sites in liver microsomes. The K-a values of tranylcypromine varied from 4.5 to 15.1 muM and -34.3 to 167 muM in microsomes derived from three different livers and of cycloprop ylbenzene from -1.6 to 10.1 muM and -34.6 and 75.2 muM in the same liver mi crosomes. Based on these results, tranylcypromine seems an adequately selec tive CYP2A6 inhibitor for in vitro use.