Inhibition of rat liver microsomal CYP1A2 and CYP2B1 activity by N-(2-heptyl)-N-methyl-propargylamine and by N-(2-heptyl)-propargylamine

(R)-N-(2-Heptyl)-N-methyl-propargylamine (R-2HMP) and (R)-N-(2-heptyl)-prop argylamine (R-2HPA) are analogs of R-deprenyl. R-Deprenyl, a selective mono amine oxidase B inhibitor, is a mechanism-based inactivator of purified CYP 2B1. The aim of the present study was to determine whether R-2HMP and R-2HP A behaved like deprenyl with respect to inhibiting cytochrome P450 (CYP450) enzyme activity. The activities of CYP1A2 and CYP1A1 were assessed by meas uring the deethylation of 7-ethoxyresorufin by liver microsomes obtained fr om control and beta -naphthoflavone-treated female Wistar rats, respectivel y. CYP2B1 activity was assessed by measuring depentylation of 7-pentoxyreso rufin by liver microsomes obtained from phenobarbital-treated rats. The act ivity of CYP1A1 was unaffected by 100 muM concentrations of R-deprenyl, R-2 HMP, or R-SHPA. In contrast, the activities of CYP1A2 and CYP2B1 were signi ficantly decreased. In general, the percentage of CYP1A2 activity remaining in the presence of 100 muM of one of these propargylamines ranged from 45 to 56%, whereas 10% or less of CYP2B1 activity remained. No marked differen ces between the various propargylamines were observed. The IC50 values for the inhibition of CYP2B1 activity by R-deprenyl, R-2HMP, and R-2HPA were fo und to be 2.6, 8.5, and 3.6 muM, respectively. The S-enantiomers of depreny l, 2HMP, and 2HPA also inhibited the activity of microsomal CYP2B1. R-2HMP, R-2HPA, and S-2HPA were found to be mechanism-based inactivators of CYP2B1 activity. The inactivation constants k(inact) and K-1 were found to be as follows: R-deprenyl, 1.3 muM and 0.32 min(-1); R-2HMP, 0.8 muM and 0.08 min (-1); R-2HPA, 0.5 muM and 0.36 min(-1); and S-2HPA, 0.24 muM and 0.18 min(- 1).