N-Methyltetrahydro-β-carboline analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin are oxidized to neurotoxic β-carbolinium cations by heme peroxidases

2-Methyl-1,2,3,4-tetrahydro-β-carboline (2-Me-THβC) and 2,9-dimethyl-1,2,3,4-tetrahydro-β-carboline (2,9-diMe-THβC) are naturally occurring analogs of the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), whereas their corresponding aromatic 2-methyl-β-carbolinium cations resemble 1-methyl-4-phenylpyridinium (MPP+) and are considered potential toxins involved in Parkinson’s disease (PD). To become toxicants, 2-methyltetrahydro-β-carbolines need to be oxidized (aromatized) by human metabolic enzymes to pyridinium-like (β-carbolinium) cations as occur with MPTP/MPP+ model. In contrast to MPTP, human MAO-A or -B were not able to oxidize 2-Me-THβC to pyridinium-like cations. Neither, cytochrome P-450 2D6 or a mixture of six P450 enzymes carried out this oxidation in a significant manner. However, 2-Me-THβC and 2,9-diMe-THβC were efficiently oxidized by horseradish peroxidase (HRP), lactoperoxidase (LPO), and myeloperoxidase (MPO) to 2-methyl-3,4-dihydro-β-carbolinium cations (2-Me-DHβC+, 2,9-diMe-DHβC+) as the main products, and detectable amount of 2-methyl-β-carbolinium cations (2-Me-βC+, 2,9-diMe-βC+). The apparent kinetic parameters (kcat, k4) were similar for HRP and LPO and higher for MPO. Peroxidase inhibitors (hydroxylamine, sodium azide, and ascorbic acid) highly reduced or abolished this oxidation. Although MPTP was not oxidized by peroxidases; its intermediate metabolite 1-methyl-4-phenyl-2,3-dihydropyridinium cation (MPDP+) was efficiently oxidized to MPP+ by heme peroxidases. It is concluded that heme peroxidases could be key catalysts responsible for the aromatization (bioactivation) of endogenous and naturally occurring N-methyltetrahydro-β-carbolines and related protoxins to toxic pyridinium-like cations resembling MPP+, suggesting a role for these enzymes in toxicological and neurotoxicological processes.