Metabolism of putative neurotoxins by allelic variants of cytochrome P450 2D6.

摘要

Cytochrome P450 2D6 (debrisoquine 4-hydroxylase), a member of the P450 family was among the first P450 polymorphisms discovered with 2 discernable phenotypes according to the ability to metabolize debrisoquine: extensive metabolizers (EM) and poor metabolizers (PM). The PM phenotype is known to be composed of various allelic variants that have an increased risk for developing PD. The PM phenotype is also believed to have a severely compromised ability to metabolize xenobiotics. One such toxin is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which is metabolized by WT P450 2D6. MPTP, an inadvertent contaminant of a synthetic opiate, which was found cause an irreversible Parkinson-like syndrome. MPTP is oxidized by monoamine oxidase-B (MAO-B) to the eventual toxin 1-methyl-4-phenylpyridinium (MPP+) that elicits a toxic response by a variety of mechanisms.;2-Methyl-beta-carbolinium (2MebetaC+) and 2-methyl isoquinolinium (MeIQ+), which possess structures similar to (MPP+), also exhibit neurotoxic effects both in vitro and in vivo. Unlike the synthetic toxin MPTP, these beta-carboline and isoquinoline analogs can be formed endogenously. These analogs are found in various foodstuffs and are found at elevated levels in Parkinson's patients.;The current study investigated if a difference in the metabolic properties of the allelic variants of 2D6 existed, especially towards the metabolism of neurotoxic beta-carboline and isoquinoline analogs. The metabolic pathways for all the substrates are described. The metabolic property of one of the allelic variants (2D6 [S486T]) was compared with that of the WT enzyme.