MPTP, the neurotoxin inducing parkinson's disease, is a potent competitive inhibitor of human and rat cytochrome P450 isozymes (P450bufI, P450db1) catalyzing debrisoquine 4-hydroxylation

doi:10.1016/S0006-291X(87)80252-8

Biochemical and Biophysical Research Communications

Volume 148, Issue 3, 13 November 1987, Pages 1144-1150

https://doi.org/10.1016/S0006-291X(87)80252-8 Get rights and content

In human liver microsomal preparations the neurotoxic chemical N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and several of its analogs competitively inhibited bufuralol l′-hydroxylase activity of cytochrome P450bufI. This enzyme is the target of the common genetic polymorphism of drug oxidation known as debrisoquine polymorphism. Bufuralol l′-hydroxylase activity was detectable in rat brain tissue. The activity was inhibited by antisera raised against a rat liver cytochrome P450 called P450dbl. Immunoblotting experiments revealed the presence of a protein in rat and human brain microsomes with the same electrophoretic properties as the liver enzyme. These data suggest that P450bufI may be involved in the metabolism and neurotoxicity of MPTP.

References (28)

MahgoubA. et al.
Lancet
(1977)
DayerP. et al.
Biochem. Biophys. Res. Commun.
(1984)
DavisG.C. et al.
Psychiatr. Res.
(1979)
MeierP.J. et al.
Gastroenterology
(1983)
LowryO.H. et al.
J. Biol. Chem.
(1951)
HauriH.P. et al.
Anal. Biochem.
(1986)
OhkuboS. et al.
Lancet
(1985)
EichelbaumM. et al.
Eur. J. Clin. Pharmacol.
(1979)
DayerP. et al.
Eur. J. Drug Metab. Pharmacokinet.
(1982)
EichelbaumM.
Clin. Pharmacokinet.
(1982)

KalowW.

Can. J. Physiol. Pharmacol.

(1982)

ParkB.K.

Br. J. Clin. Pharmacol.

(1982)

NebertD.W.

Br. Med. J.

(1981)

BarbeauA. et al.

Lancet

(1985)

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Furthermore, we speculate that our use of midazolam and (S)-ketamine anesthesia prior to MPTP-injections to increase safety of the staff handling MPTP, which the other reported MPTP minipig studies did not apply, might have protected the minipigs against extensive fiber loss. Midazolam and MPTP are both competitive inhibitors of various cytochrome P450 isozymes, that are involved in the neurotoxicity of MPTP (Fonne-Pfister et al., 1987; Wandel et al., 1994). Furthermore, a recent study found that (R)-ketamine attenuated MPTP-induced reduction in striatal dopamine transporter (DAT) and TH, while (S)-ketamine only had a small effect on DAT (Fujita et al., 2020).
The Göttingen minipig is a large animal with a gyrencephalic brain that expresses –complex behavior, making it an attractive model for Parkinson’s disease research. Here, we investigate the temporal evolution of presynaptic dopaminergic function for 14 months after injections of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the minipig using a multi-tracer longitudinal positron emission tomography (PET) design. We injected seven sedated minipigs with 1–2 mg/kg of MPTP, and two with saline, three times a week over four weeks. We monitored behavioral deficits using a validated motor scale and walking mat. Brains were imaged with (+)-⍺-[¹¹C]-dihydrotetrabenazine ([¹¹C]-DTBZ) and [¹⁸F]-dihydroxyphenylalanine ([¹⁸F]-FDOPA) PET at baseline and 1, 3, 10 and 14 months after MPTP injection, and immunohistochemistry was used to assess nigral cell loss. The minipigs showed mild bradykinesia and impaired coordination at early timepoints after MPTP. PET revealed decreases of striatal [¹¹C]-DTBZ and [¹⁸F]-FDOPA uptake post-MPTP with partial spontaneous recovery of [¹⁸F]-FDOPA after 10 months. Postmortem analysis estimated an MPTP-induced nigral loss of 57% tyrosine hydroxylase+ and 43% Nissl-stained cells. Normal motor function despite substantial damage to the dopaminergic system is consistent with prodromal Parkinson’s disease, and offers an opportunity for testing disease-modifying therapies. However, partial spontaneous recovery of dopamine terminal function must be taken into account in future studies.
CYP2D6 phenotypes and Parkinson's disease risk: A meta-analysis
2014, Journal of the Neurological Sciences
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In fact, increasing evidence has been found to reveal the function of CYP2D6 in the development of PD. Initial support includes the observation that MPTP [48], a substrate of CYP2D6, causes dopaminergic neuronal damage and Parkinsonian symptoms. In addition, CYP2D6 is localized in the substantia nigra part of the brain, which is an area involved in PD [49], and CYP2D6 has been shown to metabolize neurotransmitters, including dopamine and serotonin, as well as a variety of CNS-acting drugs including antidepressants, neuroleptics, and analgesics [50].
CYP2D6 polymorphisms have been reported to be associated with Parkinson's disease (PD) susceptibility, but the results of these previous studies were inconsistent.
To explore whether PD patients with CYP2D6 gene variation have different risk to PD to those with normal function of CYP2D6.
Systematic review with meta-analysis of case-controlled studies on the association between CYP2D6 and PD risk was conducted. Studies published up to August 1, 2013 were identified by searching electronic databases PubMed and Embase. Odds ratios (ORs) together with their corresponding 95% confidence intervals (CIs) were used to estimated the association between CYP2D6 polymorphisms and PD risk in different phenotype models. Meta-regression, subgroup analysis, sensitivity analysis and publication bias were also performed.
A total of 3521 PD Patients and 4476 controls from 29 case–control studies were identified. Overall, a borderline significant influence of the CYP2D6 polymorphisms on PD risk was observed (OR: 1.07, 95%CI: 0.99–1.16, p = 0.106). Significant association was found when comparisons were performed in different phenotypes in PM versus EM (OR = 1.33, 95% CI = 1.01–1.74, p = 0.044) and PM versus IM + EM (OR = 1.32, 95% CI = 1.11–1.56, p = 0.002). In subgroup analysis stratified by country, significant association was demonstrated in British but not in other white subjects. No significant association was detected in subgroup analysis according to the age of onset and the source of patients.
The present meta-analysis demonstrated that the poor metabolizer phenotype of CYP2D6 confers a significant genetic susceptibility to PD in Caucasians, especially in British white subjects.
Cytochrome p450 Part 2. What Nurses Need to Know About the Cytochrome p450 Family Systems.
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Citation Excerpt :
However, numerous studies have shown that differences in neurotransmitters or neuromodulatory amines account for differences in personalities among individuals with different CYP2D6 phenotypes. There are variant expressions of CYP2D6 in the human brain51 and a clinical association of CYP2D6 phenotypes with Parkinson disease.52 Although first identified in the liver, CYP2E has been found in many extrahepatic tissues including the brain, nasal mucosa, lungs, kidneys, breast, ovary, and stomach.53–55
Nicotine and caffeine-mediated modulation in the expression of toxicant responsive genes and vesicular monoamine transporter-2 in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease phenotype in mouse
2008, Brain Research
Citation Excerpt :
MPTP has been widely used to understand the molecular mechanism of neurodegeneration, and to assess the effect of neuroprotective agents (Xu et al., 2005; Bezard et al., 1997; Schmidt and Ferger, 2001). Comparative hydroxylation and N-demethylation of MPTP have shown that CYP2D6 induces MPTP detoxification and metabolism (Herraiz et al., 2006; Fonne-Pfister et al., 1987; Gilham et al., 1997). Diethyl-di-thiocarbamate-mediated enhancing effect in wild-type animals on MPTP-induced toxicity and lack of such effect in CYP2E1 knockout mice have suggested that CYP2E1 plays a critical role in the detoxification of neurotoxins (Vaglini et al., 2004).
Epidemiological evidence revealed that cigarette smokers and coffee drinkers have lower risk of Parkinson's disease (PD). Nicotine inhibits monoamine oxidase activity, and induces expression of neurotrophic factors and nicotinic acetylcholinergic receptors. However, caffeine is capable of antagonizing adenosine A_2A receptor. Toxicant responsive enzymes and vesicular monoamine transporter-2 (VMAT-2) play critical roles in chemically induced PD. Despite some known functions, the effects of nicotine and caffeine on the expression and activity of toxicant responsive genes and on VMAT-2 are still not known. The study was therefore undertaken to investigate the effect of nicotine and caffeine on the expression and activity of toxicant responsive genes, i.e., CYP1A1, CYP2E1, GST-ya, GST-yc, GSTA4-4 and VMAT-2 in the striatum of control and MPTP-induced PD phenotype in mouse. The animals were treated intraperitoneally daily with nicotine (1 mg/kg) or caffeine (20 mg/kg) for 8 weeks, followed by 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 20 mg/kg) + nicotine or caffeine for 4 weeks. MPTP significantly attenuated CYP1A1 and VMAT-2, and augmented CYP2E1, GST-ya, GST-yc and GSTA4-4 expression/activity. Nicotine or caffeine-treated animals showed significant restoration against most of the MPTP-induced alterations. The results obtained thus suggest that nicotine and caffeine modulate MPTP-induced alterations in CYP1A1, CYP2E1, GST-ya, GST-yc, GSTA4-4 and VMAT-2 expression/activity.
Cytochrome P450-catalyzed pathways in human brain: Metabolism meets pharmacology or old drugs with new mechanism of action?
2007, Pharmacology and Therapeutics
The true importance of cytochrome P450 enzymes, not just in drug metabolism but also in pharmacology, is only beginning to be appreciated. Though originally discovered through their role in the biotransformation of xenobiotics, the P450 enzyme super family is ubiquitous in nature and necessarily evolved around endogenous pathways. The extent of tissue- and cell-specific expression of individual P450 isoforms has led many investigators to hypothesize localized roles in endogenous biochemical pathways for isoforms traditionally thought of as drug-metabolizing. In some cases, direct evidence from humanized transgenic animal models can confirm the degree to which such enzymes modulate endogenous pathways. However, overlapping P450 substrate specificities may mask genetic or biochemical deficiencies, such that many of these reactions appear nonessential. Nonetheless, the drug-induced alteration of local biochemical concentrations in extrahepatic tissues due to metabolism by and inhibition of P450 isoforms has tremendous potential for introducing unexpected pharmacological effects. Nowhere is this truer than in the CNS. On the other hand, if we can harness the power of in silico modeling to create highly specific inhibitors of identified brain isoforms, a novel avenue for drug design using P450 as drug targets may be at hand. This article highlights some notable examples in which the catalytic state of specific P450 isoforms involved in endogenous biochemical reaction pathways are influenced by pharmacological agents. The implications of inhibition of P450-catalzyed oxidation steps that are known or speculated to influence arachadonic acid, cholesterol, and catecholamine neurotransmitters pathways in human brain will be considered.
Comparative aromatic hydroxylation and N-demethylation of MPTP neurotoxin and its analogs, N-methylated β-carboline and isoquinoline alkaloids, by human cytochrome P450 2D6
2006, Toxicology and Applied Pharmacology
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin is a chemical inducer of Parkinson's disease (PD) whereas N-methylated β-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 K_m of 79.36 ± 3 μM (formation of MPTP-OH) and 18.95 min^− 1 and K_m 69.6 ± 2.2 μM (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 β-carbolines and isoquinolines were screened for N-demethylation (detoxification) that was not significantly catalyzed by CYP2D6 or the P450s mixture. In contrast, various β-carbolines were efficiently hydroxylated to hydroxy-β-carbolines by CYP2D6. Thus, N(2)-methyl-1,2,3,4-tetrahydro-β-carboline (a close MPTP analog) was highly hydroxylated to 6-hydroxy-N(2)-methyl-1,2,3,4-tetrahydro-β-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-β-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 β-carbolines.

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MPTP, the neurotoxin inducing parkinson's disease, is a potent competitive inhibitor of human and rat cytochrome P450 isozymes (P450bufI, P450db1) catalyzing debrisoquine 4-hydroxylation

Lancet

Biochem. Biophys. Res. Commun.

Psychiatr. Res.

Gastroenterology

J. Biol. Chem.

Anal. Biochem.

Lancet

Eur. J. Clin. Pharmacol.

Eur. J. Drug Metab. Pharmacokinet.

Clin. Pharmacokinet.

Can. J. Physiol. Pharmacol.

Br. J. Clin. Pharmacol.

Br. Med. J.

Lancet