1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP)
neurotoxin is a chemical inducer of
Parkinson's disease (PD) whereas N-methylated
beta-carbolines and
isoquinolines are naturally occurring analogues of
MPTP involved in PD. This research has studied the oxidation of
MPTP by human
CYP2D6 (
CYP2D6*1 and
CYP2D6*10 allelic variants) as well as by a mixture of
cytochrome P450s-resembling HLM, and the products generated compared with those afforded by human
monoamine oxidase (
MAO-B).
MPTP was efficiently oxidized by
CYP2D6 to two main products:
MPTP-
OH (p-hydroxylation) and PTP (N-demethylation), with turnover numbers of 10.09 min-1 and Km of 79.36+/-3 microM (formation of
MPTP-
OH) and 18.95 min-1 and Km 69.6+/-2.2 microM (PTP). Small amounts of dehydrogenated toxins MPDP+ and MPP+ were also detected.
CYP2D6 competed with
MAO-B for the oxidation of
MPTP.
MPTP oxidation by
MAO-B to MPDP+ and MPP+ toxins (bioactivation) was up to 3-fold higher than
CYP2D6 detoxification to PTP and
MPTP-
OH. Several N-methylated
beta-carbolines and
isoquinolines were screened for N-demethylation (detoxification) that was not significantly catalyzed by
CYP2D6 or the P450s mixture. In contrast, various
beta-carbolines were efficiently hydroxylated to hydroxy-
beta-carbolines by
CYP2D6. Thus, N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline (a close
MPTP analog) was highly hydroxylated to 6-hydroxy-N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline and a corresponding 7-hydroxy-derivative. Thus,
CYP2D6 could participate in the bioactivation and/or detoxification of these neuroactive compounds by an active hydroxylation pathway. The
CYP2D6*1 enzymatic variant exhibited much higher metabolism of both
MPTP and N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline than the
CYP2D6*10 variant, highlighting the importance of
CYP2D6 polymorphism in the oxidation of these toxins. Altogether, these results suggest that
CYP2D6 can play an important role in the metabolic outcome of both
MPTP and
beta-carbolines.