Cytochrome P450-dependent Metabolism of L-deprenyl in the Brain of Different Experimental Mammals

Although the CYP content of brain is too low to significantly influence the overall pharmaco-kinetics of drugs and hormones in the body, brain CYP could play a role in tissue-and/or cell-specific sensitivity to certain drugs or xenobiotics. We have characterized the CYP-dependent metabolism of l-deprenyl by brain microsomal preparations obtained from different experimental animals: monkey, C57BL/6 mouse and rabbit. In monkey the kinetic analysis revealed a similar methamphetamine and nordeprenyl formation from l-deprenyl in striatum and cortex. Both metabolic pathways appeared to be more efficient in the cortex than in the striatum, since the V max for microsomal preparations was lower in the striatum for the formation of both metabolites. Inhibition analysis suggested that l-methamphetamine formation is catalysed by CYP2A and CYP3A, whereas only CYP3A appears to be involved in nordeprenyl formation. The kinetic study performed with microsomal preparations from whole brain of C57BL/6 mice highlighted that the only detectable l-deprenyl metabolite was methamphetamine with K m and V max values similar to those determined in monkey cortex. However, the inhibition studies suggested the involvement of CYP2E1. In rabbit the apparent K m value of both metabolic pathways obtained using whole brain microsomal preparations resulted about five fold higher to the values observed in previous mammalian preparations. Inhibition studies suggested the involvement of CYP2A family in deprenyl metabolism. In conclusion, the present study indicates that l-deprenyl is effectively metabolised by CYP-dependent oxidases in the brain, giving rise mainly to the formation of methamphetamine and that there are differences between species in CYP-dependent metabolism of l-deprenyl.