Home
JournalsCollections
For Authors For Reviewers For Editorial Board Members
Article Processing Charges Open Access
Ethics Advertising Policy
Editorial Policy Resource Center
Company Information Contact Us
OPEN ACCESS

Flavin-containing Monooxygenases in the Brain and their Involvement in Neurodegeneration and Aging

  • Boyu Li and
  • Zhuoling An* 
Journal of Exploratory Research in Pharmacology   2023;8(3):237-241

doi: 10.14218/JERP.2022.00067

Received:

Revised:

Accepted:

Published online:

 Author information

Citation: Li B, An Z. Flavin-containing Monooxygenases in the Brain and their Involvement in Neurodegeneration and Aging. J Explor Res Pharmacol. 2023;8(3):237-241. doi: 10.14218/JERP.2022.00067.

Abstract

Flavin-containing monooxygenases (FMOs) catalyze the oxygenation of a diverse range of sulfur or nitrogen-containing xenobiotics. Recently accumulated evidence has demonstrated the roles of FMOs in physiological and pathological conditions, including neurodegeneration and aging. However, the mechanisms underlying their functions are poorly understood. In this review, we summarize the expression and localization of FMOs in the brain, the endogenous chemicals and xenobiotics metabolized by FMOs, and the consequences of FMO deficiency. The understanding of FMOs activity in the brain is important for fully elucidating the roles of FMOs in pathological mechanisms.

Keywords

Flavin-containing monooxygenases (FMOs), Brain, Expression, Location, Substrates, Deficiency, Neurodegeneration and aging

Introduction

Flavin-containing monooxygenases (FMOs) constitute a family of microsomal enzymes catalyzing the oxidation of nucleophilic heteroatom-containing xenobiotics.1 They oxygenate the sulfur or nitrogen atoms in chemicals with soft nucleophiles.2 FMOs are involved in the pathogenic process of trimethylaminuria, atherosclerosis, cardiovascular disease, diabetes, and metabolic disorders.3–6 In recent years, the involvement of FMOs in neurodegeneration and aging has emerged,7 but the underlying mechanisms have not been elucidated. In this review, we summarize the expression and localization of FMOs in the brain, the endogenous chemicals and xenobiotics metabolized by FMOs in the brain, and the consequences of FMO deficiency.

FMO

FMO (EC 1.14.13.8) was first described by Ziegler et al.8,9 Humans possess five functional FMO genes, designated FMO1–5. FMO1–4 are clustered on chromosome 1 q24.3, and FMO5 is located at 1q21.1.10,11 Numerous allelic variants, including approximately 20 of human FMO1, have been reported.12

Mammalian FMOs are NADPH- and oxygen-dependent microsomal monooxygenases that usually metabolize nitrogen- and sulfur-containing compounds.1,13,14 The catalytic mechanism involves a first step in which FAD undergoes a 2-electron reduction by NADPH. The reduced flavin then reacts rapidly with molecular oxygen to form peroxyflavin. This nucleophilic attack by the substrate on FADOOH results in the transfer of one atom of molecular oxygen to the substrate with another contributing to the formation of water.

Trimethylaminuria is a currently confirmed rare inherited metabolic disorder associated with abnormal amounts of dietary-derived trimethylamine and is caused by the mutations in FMO3.15,16

Emerging roles of FMOs in neurodegeneration and aging

Amyotrophic lateral sclerosis

Association between FMOs and amyotrophic lateral sclerosis (ALS) has been widely reported although some reports are contradictory. Malaspina et al.17 reported an 80% reduction in FMO1 mRNA levels in the spinal cord of sporadic ALS patients. In contrast, Gagliardi et al.18 observed greater FMO1 expression in the spinal cord and brain stem of ALS patients compared with that in healthy controls. Gagliardi et al.19 found that the mRNA levels of all FMOs except for FMO3 were up-regulated in the brain of SOD1-mutated (G93A) ALS mice compared with control mice, with the highest increase in FMO1 in the spinal cord and brainstem. Cereda et al.12 found a significantly elevated frequency of FMO1 single nucleotide polymorphisms in female sporadic ALS patients, further indicating that specific allelic variants of FMO1 might be associated with ALS development.

Parkinsonism

Accumulating evidence indicates a relationship between FMOs and parkinsonism. The FMO gene cluster is associated with the volume of the lentiform nucleus, which is a physiological marker associated with Parkinson’s disease (PD). Nicotine can be N-oxidized by FMOs and can reduce oxidative stress and neuro-inflammation in the brain and improve synaptic plasticity and neuronal survival of dopaminergic (DA) neurons, thereby benefiting PD patients.20,21 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin and its toxic metabolite 1-methyl-4-phenylpyridinium (MPP+) can kill DA neurons and elicit parkinsonism. MPTP can be deactivated by FMOs into a harmless metabolite in the brain (discussed in detail in the section, Endogenous Substances and Xenobiotics Oxygenated by FMOs in the Brain). In addition, we have shown that FMO1 deficiency promotes neuroinflammation that affects the survival of DA neurons in mice. The levels of FMO1 mRNA transcripts decreased in a rotenone model of parkinsonism, accompanied by decreasing levels of parkin mRNA transcripts and increased Caspase-3 activation.22,23

Aging

FMO1–5 have all been reported to be transcriptionally activated in classical mouse models of longevity, including calorie restriction, growth hormone/insulin-like growth factor 1 signaling disruption, and rapamycin treatment.7 The expression of FMO3 is up-regulated in the liver of a variety of longevity mouse models.24–27 However, up-regulation of FMO3 expression in hepatocytes of murine models has recently been shown to prevent or reverse hepatic aging. This mimicked calorie restriction and the associated mechanism is probably attributed to the promotion of autophagy.28 Furthermore, feeding with a normal diet significantly down-regulated FMO1 mRNA transcripts in mice in an age-dependent manner,29 indicating that reduced FMO1 expression contributes to the progression of aging. However, the specific mechanism underlying its role is still unknown.

The expression and localization of FMOs in the brain

The mRNAs of mammalian FMO isoforms can be detected in different organs, including the liver, kidney, lung, and brain.30 FMOs are active in human, rat, mouse, rabbit, hamster, and guinea pig brains.31–37 Here we mainly review FMO activity in mouse and human brains.

Mouse brain

In an adult mouse brain, FMO1 and 5 are the most abundant FMOs, as detected using isoform-specific antisense RNA probes.30FMO1 mRNA transcripts are observed in neurons of the cerebrum and the choroid plexus while FMO5 mRNA transcripts are only detected in neurons of the cerebrum. FMO expression in astrocytes remains controversial. Janmohamed et al.30 reported no detectable FMO activity in vivo, while Di Monte et al.38 detected FMO activity in primary cultures of mouse astrocytes.

In the neonatal brain, the most abundant FMO mRNA transcripts are FMO1, and their level drops by approximately 80% at 8 weeks of age. The levels of FMO5 mRNA transcripts are 70% of FMO1 in neonates and are similar to that of FMO1 in 3-, 5- and 8-week-old mouse brains. FMO2, 3, and 4 mRNA transcripts are present at relatively low levels; approximately <1 molecule/cell.

Human brain

Zhang et al.34 examined the developmental expression of FMOs in 60 human brain samples detecting all FMO15 mRNA transcripts. FMO mRNA levels in the brain were much lower than that in other tissues, about less than 1% compared with the most abundant tissues observed (i.e., FMO1 in the kidney, FMO2 in the lung, and FMO3 and 5 in the liver). FMO1 is the only subtype to be down-regulated in adult human brains, while the amounts of other FMO mRNA transcripts in human brains remain similar among different age groups. Few studies have reported the expression of FMOs in human brains. Cashman et al.39 found that FMO3 was selectively expressed in the substantia nigra of human brains by immunohistochemistry.

Endogenous substances and xenobiotics oxygenated by FMOs in the brain

Endogenous substances

FMO catalyzes the N- and S-oxygenation of several endogenous substances, including phenethylamine, tyramine, amphetamine, and trimethylamine that can be converted by FMO in the brain with clinical significance.40 S-oxygenation of hypotaurine by FMO1 contributes to the production of taurine in the brain, which possesses neurotransmitter, antioxidant, and anti-inflammatory functions.41

Xenobiotics

FMO oxidizes particular xenobiotics in the brain. Nicotine, which is abundant in tobacco smoke and can diminish oxidative stress and neuroinflammation in the brain, is hydroxylated by CYP2A6 and undergoes glucuronidation by UDP-glucuronosyl transferases and oxidation by FMO.21,42,43 Several psychoactive drugs, e.g. imipramine, chlorpromazine, and fluoxetine, are N- or S-oxygenated by FMO in both rat and human brains.31,32,44 Imipramine causes greater sedation in wild-type animals compared with FMO1-null mice, probably because imipramine N-oxide is produced in the wild-type brain and a higher concentration of desipramine is produced in the FMO1-null brain.45

A typical xenobiotic oxidized by FMO is the pro-neurotoxin, MPTP, which can lead to DA neuron degeneration and parkinsonism in humans.46–48 MPTP in the brain is rapidly converted to the toxic MPP+49,50 by monoamine oxidase B51,52 or CYP (marmoset CYP2D6 and human CYP1A2).47,49,53 However, MPTP can be deactivated to 4-phenyl-1,2,3,6-tetrahydropyridine (PTP) and MPTP N-oxide that is non-neurotoxic, by CYP2D6 and FMO (Fig. 1).53–55 The concentrations of MPP+ in Suncus brains after a single intraperitoneal administration of MPTP were markedly higher than that in rats, probably because of the lack of FMO activity in Suncus brains.56 FMO1 and 3 may contribute to this detoxification. MPTP N-oxygenation in human brain microsomes was consistently catalyzed by human FMO1 and 3.53

Metabolic activation and deactivation of MPTP.
Fig. 1  Metabolic activation and deactivation of MPTP.

Activation: MPTP was rapidly converted to the toxic metabolite MPP+ through the intermediate MPDP+ once in the brain mediated by monoamine oxidase B or CYP (marmoset CYP2D6 and human CYP1A2). Deactivation: MPTP N-oxygenation was efficiently mediated by FMOs in marmoset liver and brain microsomes. PTP formation was efficiently mediated by CYP2D6 in marmoset liver microsomes. FMOs, flavin-containing monooxygenases; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+, 1-methyl-4-phenylpyridinium; PTP, 4-phenyl-1,2,3,6-tetrahydropyridine; CYP, cytochrome P450.

What are the consequences of FMO deficiency?

Genetic deficiency of FMOs has several consequences. FMO1 deficiency promotes neuroinflammation that affects the survival of DA neurons in C57BL/6N mice.23 Mice with FMO1, 2, and 4 deficiency exhibit a lean phenotype and enhanced resting energy expenditure, those with FMO1 deficiency most likely underlying the metabolic phenotype.57 FMO3 is a target of insulin and knockdown of FMO3 expression in insulin-resistant mice improves glucose tolerance.6 Knockdown of FMO3 expression in the liver of low-density lipoprotein receptor-knockout mice leads to decreased circulating trimethylamine N-oxide (TMAO) levels (an independent risk factor for cardiovascular disease) and atherosclerosis.4,5Fmo5−/− mice exhibit a lean phenotype and are resistant to age-related changes in glucose homeostasis compared with wild-type mice, indicating that FMO5 is a regulator of metabolic aging.58Fmo5−/− mice also possess metabolic characteristics similar to those of germ-free mice, indicating that FMO5 is crucial for sensing or responding to gut bacteria.59 However, conditional knockdown of brain FMOs has not been reported.

Further directions

The precise roles of FMOs in pathological processes remain to be determined. In-depth knowledge of FMO gene expression and protein localization and identification of substrates in the brain that are oxidized by FMOs may help in understanding the mechanisms of action of FMOs and their importance in the pathogenesis of neuronal degeneration and aging.

Conclusions

The potential involvement of FMOs in neurodegeneration and aging has been demonstrated in recent years. FMOs play important roles in metabolizing certain endogenous chemicals and xenobiotics in the brain, which participate in physiological and pathological processes. Knowledge of the expression and localization of FMOs in the brain, the endogenous chemicals and xenobiotics metabolized by FMOs, and the consequences of FMO deficiency can help us understand their involvement in neurodegeneration and aging.

Abbreviations

ALS: 

amyotrophic lateral sclerosis

CYP: 

cytochrome P450

FMOs: 

flavin-containing monooxygenases

MPP+

1-methyl-4-phenylpyridinium

MPTP: 

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PD: 

Parkinson’s disease

PTP: 

4-phenyl-1,2,3,6-tetrahydropyridine

TMAO: 

trimethylamine N-oxide

NADPH: 

nicoti namide adenine dinucleotide phosphate oxidase

FAD: 

flavin adenine dinucleotide

Declarations

Acknowledgement

We thank Dr. Shifeng Chu for his helpful advice and Jinglin Wang, Bingqing Ren, Linxi Zhang for their involvement in discussions.

Funding

This work was supported by (1) The National Natural Science Foundation of China (Grant no. 81803500), (2) The Beijing Hospitals Authority Innovation Studio of Young Staff Funding Support (code 202108), and (3) The Undergraduate Scientific Research Training Program (XSKY2022).

Conflict of interest

The authors declare no conflict of interests.

Authors’ contributions

Writing of the original draft (BL); supervision (ZA).

References

  1. Phillips IR, Shephard EA. Drug metabolism by flavin-containing monooxygenases of human and mouse. Expert Opin Drug Metab Toxicol 2017;13(2):167-181 View Article PubMed/NCBI
  2. Cashman JR. Role of flavin-containing monooxygenase in drug development. Expert Opin Drug Metab Toxicol 2008;4(12):1507-1521 View Article PubMed/NCBI
  3. Fennema D, Phillips IR, Shephard EA. Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease. Drug Metab Dispos 2016;44(11):1839-1850 View Article PubMed/NCBI
  4. Shih DM, Wang Z, Lee R, Meng Y, Che N, Charugundla S, et al. Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. J Lipid Res 2015;56(1):22-37 View Article PubMed/NCBI
  5. Shih DM, Zhu W, Schugar RC, Meng Y, Jia X, Miikeda A, et al. Genetic Deficiency of Flavin-Containing Monooxygenase 3 ( Fmo3) Protects Against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels-Brief Report. Arterioscler Thromb Vasc Biol 2019;39(6):1045-1054 View Article PubMed/NCBI
  6. Miao J, Ling AV, Manthena PV, Gearing ME, Graham MJ, Crooke RM, et al. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat Commun 2015;6:6498 View Article PubMed/NCBI
  7. Rossner R, Kaeberlein M, Leiser SF. Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes. J Biol Chem 2017;292(27):11138-11146 View Article PubMed/NCBI
  8. Ziegler DM. Flavin-containing monooxygenases: catalytic mechanism and substrate specificities. Drug Metab Rev 1988;19(1):1-32 View Article PubMed/NCBI
  9. Poulsen LL, Ziegler DM. Multisubstrate flavin-containing monooxygenases: applications of mechanism to specificity. Chem Biol Interact 1995;96(1):57-73 View Article PubMed/NCBI
  10. Phillips IR, Dolphin CT, Clair P, Hadley MR, Hutt AJ, McCombie RR, et al. The molecular biology of the flavin-containing monooxygenases of man. Chem Biol Interact 1995;96(1):17-32 View Article PubMed/NCBI
  11. Hernandez D, Janmohamed A, Chandan P, Phillips IR, Shephard EA. Organization and evolution of the flavin-containing monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters. Pharmacogenetics 2004;14(2):117-130 View Article PubMed/NCBI
  12. Cereda C, Gabanti E, Corato M, de Silvestri A, Alimonti D, Cova E, et al. Increased incidence of FMO1 gene single nucleotide polymorphisms in sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2006;7(4):227-234 View Article PubMed/NCBI
  13. Krueger SK, Williams DE. Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther 2005;106(3):357-387 View Article PubMed/NCBI
  14. Cashman JR. Structural and catalytic properties of the mammalian flavin-containing monooxygenase. Chem Res Toxicol 1995;8(2):166-181 View Article PubMed/NCBI
  15. Treacy EP, Akerman BR, Chow LM, Youil R, Bibeau C, Lin J, et al. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet 1998;7(5):839-845 View Article PubMed/NCBI
  16. Cashman JR, Camp K, Fakharzadeh SS, Fennessey PV, Hines RN, Mamer OA, et al. Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Curr Drug Metab 2003;4(2):151-170 View Article PubMed/NCBI
  17. Malaspina A, Kaushik N, de Belleroche J. Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays. J Neurochem 2001;77(1):132-145 View Article PubMed/NCBI
  18. Gagliardi S, Abel K, Bianchi M, Milani P, Bernuzzi S, Corato M, et al. Regulation of FMO and PON detoxication systems in ALS human tissues. Neurotox Res 2013;23(4):370-377 View Article PubMed/NCBI
  19. Gagliardi S, Ogliari P, Davin A, Corato M, Cova E, Abel K, et al. Flavin-containing monooxygenase mRNA levels are up-regulated in als brain areas in SOD1-mutant mice. Neurotox Res 2011;20(2):150-158 View Article PubMed/NCBI
  20. Barreto GE, Iarkov A, Moran VE. Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease. Front Aging Neurosci 2014;6:340 View Article PubMed/NCBI
  21. Perez-Paramo YX, Chen G, Ashmore JH, Watson CJW, Nasrin S, Adams-Haduch J, et al. Nicotine-N′-Oxidation by Flavin Monooxygenase Enzymes. Cancer Epidemiol Biomarkers Prev 2019;28(2):311-320 View Article PubMed/NCBI
  22. Li B, Yuan Y, Zhang W, He W, Hu J, Chen N. Flavin-containing monooxygenase, a new clue of pathological proteins in the rotenone model of parkinsonism. Neurosci Lett 2014;566:11-16 View Article PubMed/NCBI
  23. Li B, Yang S, Ye J, Chu S, Chen N, An Z. Flavin-containing monooxygenase 1 deficiency promotes neuroinflammation in dopaminergic neurons in mice. Neurosci Lett 2021;764:136222 View Article PubMed/NCBI
  24. Swindell WR. Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse. BMC Genomics 2009;10:585 View Article PubMed/NCBI
  25. Steinbaugh MJ, Sun LY, Bartke A, Miller RA. Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan. Am J Physiol Endocrinol Metab 2012;303(4):E488-E495 View Article PubMed/NCBI
  26. Schirra HJ, Anderson CG, Wilson WJ, Kerr L, Craik DJ, Waters MJ, et al. Altered metabolism of growth hormone receptor mutant mice: a combined NMR metabonomics and microarray study. PLoS One 2008;3(7):e2764 View Article PubMed/NCBI
  27. Swindell WR. Gene expression profiling of long-lived dwarf mice: longevity-associated genes and relationships with diet, gender and aging. BMC Genomics 2007;8:353 View Article PubMed/NCBI
  28. Guo D, Shen Y, Li W, Li Q, Miao Y, Zhong Y. Upregulation of flavin-containing monooxygenase 3 mimics calorie restriction to retard liver aging by inducing autophagy. Aging (Albany NY) 2020;12(1):931-944 View Article PubMed/NCBI
  29. Bhagwat SV, Bhamre S, Boyd MR, Ravindranath V. Cerebral metabolism of imipramine and a purified flavin-containing monooxygenase from human brain. Neuropsychopharmacology 1996;15(2):133-142 View Article PubMed/NCBI
  30. Janmohamed A, Hernandez D, Phillips IR, Shephard EA. Cell-, tissue-, sex- and developmental stage-specific expression of mouse flavin-containing monooxygenases (Fmos). Biochem Pharmacol 2004;68(1):73-83 View Article PubMed/NCBI
  31. Bhamre S, Bhagwat SV, Shankar SK, Williams DE, Ravindranath V. Cerebral flavin-containing monooxygenase-mediated metabolism of antidepressants in brain: immunochemical properties and immunocytochemical localization. J Pharmacol Exp Ther 1993;267(1):555-559 View Article PubMed/NCBI
  32. Bhamre S, Bhagwat SV, Shankar SK, Boyd MR, Ravindranath V. Flavin-containing monooxygenase mediated metabolism of psychoactive drugs by human brain microsomes. Brain Res 1995;672(1-2):276-280 View Article PubMed/NCBI
  33. Zane NR, Chen Y, Wang MZ, Thakker DR. Cytochrome P450 and flavin-containing monooxygenase families: age-dependent differences in expression and functional activity. Pediatr Res 2018;83(2):527-535 View Article PubMed/NCBI
  34. Zhang J, Cashman JR. Quantitative analysis of FMO gene mRNA levels in human tissues. Drug Metab Dispos 2006;34(1):19-26 View Article PubMed/NCBI
  35. Bhagwat SV, Bhamre S, Boyd MR, Ravindranath V. Further characterization of rat brain flavin-containing monooxygenase. Metabolism of imipramine to its N-oxide. Biochem Pharmacol 1996;51(11):1469-1475 View Article PubMed/NCBI
  36. Blake BL, Philpot RM, Levi PE, Hodgson E. Xenobiotic biotransforming enzymes in the central nervous system: an isoform of flavin-containing monooxygenase (FMO4) is expressed in rabbit brain. Chem Biol Interact 1996;99(1-3):253-261 View Article PubMed/NCBI
  37. Kawaji A, Isobe M, Takabatake E. Differences in enzymatic properties of flavin-containing monooxygenase in brain microsomes of rat, mouse, hamster, guinea pig and rabbit. Biol Pharm Bull 1997;20(8):917-919 View Article PubMed/NCBI
  38. Di Monte DA, Wu EY, Irwin I, Delanney LE, Langston JW. Biotransformation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes. J Pharmacol Exp Ther 1991;258(2):594-600 View Article PubMed/NCBI
  39. Cashman JR, Zhang J. Interindividual differences of human flavin-containing monooxygenase 3: genetic polymorphisms and functional variation. Drug Metab Dispos 2002;30(10):1043-1052 View Article PubMed/NCBI
  40. Lin J, Cashman JR. Detoxication of tyramine by the flavin-containing monooxygenase: stereoselective formation of the trans oxime. Chem Res Toxicol 1997;10(8):842-852 View Article PubMed/NCBI
  41. Veeravalli S, Phillips IR, Freire RT, Varshavi D, Everett JR, Shephard EA. Flavin-Containing Monooxygenase 1 Catalyzes the Production of Taurine from Hypotaurine. Drug Metab Dispos 2020;48(5):378-385 View Article PubMed/NCBI
  42. Hukkanen J, Jacob P, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev 2005;57(1):79-115 View Article PubMed/NCBI
  43. von Weymarn LB, Brown KM, Murphy SE. Inactivation of CYP2A6 and CYP2A13 during nicotine metabolism. J Pharmacol Exp Ther 2006;316(1):295-303 View Article PubMed/NCBI
  44. Ravindranath V, Boyd MR. Xenobiotic metabolism in brain. Drug Metab Rev 1995;27(3):419-448 View Article PubMed/NCBI
  45. Hernandez D, Janmohamed A, Chandan P, Omar BA, Phillips IR, Shephard EA. Deletion of the mouse Fmo1 gene results in enhanced pharmacological behavioural responses to imipramine. Pharmacogenet Genomics 2009;19(4):289-299 View Article PubMed/NCBI
  46. Langston JW, Ballard PA. Parkinson’s disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N Engl J Med 1983;309(5):310 View Article PubMed/NCBI
  47. Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 1985;35(7):949-956 View Article PubMed/NCBI
  48. Davis KD, Taub E, Houle S, Lang AE, Dostrovsky JO, Tasker RR, et al. Globus pallidus stimulation activates the cortical motor system during alleviation of parkinsonian symptoms. Nat Med 1997;3(6):671-674 View Article PubMed/NCBI
  49. Langston JW. The MPTP Story. J Parkinsons Dis 2017;7(s1):S11-S19 View Article PubMed/NCBI
  50. Langston JW, Irwin I, Langston EB, Forno LS. 1-Methyl-4-phenylpyridinium ion (MPP+): identification of a metabolite of MPTP, a toxin selective to the substantia nigra. Neurosci Lett 1984;48(1):87-92 View Article PubMed/NCBI
  51. Chiba K, Trevor A, Castagnoli N. Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 1984;120(2):574-578 View Article PubMed/NCBI
  52. Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC. Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 1984;311(5985):467-469 View Article PubMed/NCBI
  53. Uehara S, Uno Y, Inoue T, Murayama N, Shimizu M, Sasaki E, et al. Activation and deactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by cytochrome P450 enzymes and flavin-containing monooxygenases in common marmosets (Callithrix jacchus). Drug Metab Dispos 2015;43(5):735-742 View Article PubMed/NCBI
  54. Bajpai P, Sangar MC, Singh S, Tang W, Bansal S, Chowdhury G, et al. Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondrion-targeted cytochrome P450 2D6: implications in Parkinson disease. J Biol Chem 2013;288(6):4436-4451 View Article PubMed/NCBI
  55. Herraiz T, Guillén H, Galisteo J. Metabolite profile resulting from the activation/inactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 2-methyltetrahydro-β-carboline by oxidative enzymes. Biomed Res Int 2013;2013:248608 View Article PubMed/NCBI
  56. Mushiroda T, Ariyoshi N, Yokoi T, Takahara E, Nagata O, Kato H, et al. Accumulation of the 1-methyl-4-phenylpyridinium ion in suncus (Suncus murinus) brain: implication for flavin-containing monooxygenase activity in brain microvessels. Chem Res Toxicol 2001;14(2):228-232 View Article PubMed/NCBI
  57. Veeravalli S, Omar BA, Houseman L, Hancock M, Gonzalez Malagon SG, Scott F, et al. The phenotype of a flavin-containing monooyxgenase knockout mouse implicates the drug-metabolizing enzyme FMO1 as a novel regulator of energy balance. Biochem Pharmacol 2014;90(1):88-95 View Article PubMed/NCBI
  58. Gonzalez Malagon SG, Melidoni AN, Hernandez D, Omar BA, Houseman L, Veeravalli S, et al. The phenotype of a knockout mouse identifies flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic ageing. Biochem Pharmacol 2015;96(3):267-277 View Article PubMed/NCBI
  59. Scott F, Gonzalez Malagon SG, O’Brien BA, Fennema D, Veeravalli S, Coveney CR, et al. Identification of Flavin-Containing Monooxygenase 5 (FMO5) as a Regulator of Glucose Homeostasis and a Potential Sensor of Gut Bacteria. Drug Metab Dispos 2017;45(9):982-989 View Article PubMed/NCBI