P450 enzymes and Parkinson's disease: The story so far

Riedl, Andrew G.; Watts, Paul M.; Jenner, Peter; Marsden, C. D.

doi:10.1002/mds.870130204

Cited by 79 publications

(37 citation statements)

References 68 publications

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“…P450 26B1 and the recently described P450 46B1 are involved in the metabolism of the endogenous substances all-trans retinoic acid and cholesterol, respectively (Bogdanovic et al, 2001;Trofimova-Griffin and Juchau, 2002;Mast et al, 2003). Drugs used in treatment of common neurological and mental diseases (e.g., clozapine, phenytoin, and antidepressants) exhibit specific function in certain brain regions (Kusumi et al, 1995;Riedl et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

mRNA Distribution and Heterologous Expression of Orphan Cytochrome P450 20A1

Stark

Wu²,

Bartleson³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Cytochrome P450 (P450) 20A1 is one of the so-called "orphan" P450s without assigned biological function. mRNA expression was detected in human liver, and extrahepatic expression was noted in several human brain regions, including substantia nigra, hippocampus, and amygdala, using conventional polymerase chain reaction and RNA dot blot analysis. Adult human liver contained 3-fold higher overall mRNA levels than whole brain, although specific regions (i.e., hippocampus and substantia nigra) exhibited higher mRNA expression levels than liver. Orthologous full-length and truncated transcripts of P450 20A1 were transcribed and sequenced from rat liver, heart, and brain. In rat, the concentrations of full-length transcripts were 3-to 4-fold higher in brain and heart than in liver. In situ hybridization of rat whole brain sections showed an mRNA expression pattern similar to that observed for human P450 20A1, indicating expression in substantia nigra, hippocampus, and amygdala. A number of N-terminal modifications of the codon-optimized human P450 20A1 sequence were prepared and expressed in Escherichia coli, and two of the truncated derivatives showed characteristic P450 spectra (200-280 nmol of P450/ l). Although the recombinant enzyme system oxidized NADPH, no catalytic activity was observed with the heterologously expressed protein when a number of potential steroids and biogenic amines were surveyed as potential substrates. The function of P450 20A1 remains unknown; however, the sites of mRNA expression in human brain and the conservation among species may suggest possible neurophysiological function.P450 monooxygenases catalyze the introduction of oxygen into a vast range of molecules and are known to have diverse functions in endogenous and exogenous metabolism (Ortiz de Montellano, 2005). Cytochromes P450 (P450s) in families 1 to 3 are involved primarily in the metabolism of exogenous compounds, i.e., drugs and environmental pollutants, whereas families 4 to 51 consist of enzymes involved primarily in the bioconversion of endogenous compounds, i.e., steroids, fatty acids, vitamins, and eicosanoids (Guengerich, 2005). To date 57 human P450 (CYP or P450, P450 indicating the nucleotide or protein and CYP indicating the gene in question) genes are known (http://drnelson.utmem.edu/CytochromeP450.html). The P450s can be divided into six major groups based on their main substrates: steroids, vitamins, fatty acids, eicosanoids, xenobiotics, and unknown (Nelson et al., 1996;Guengerich et al., 2005). It is noteworthy, however, that a number of known P450s have assigned substrates in more than one of these groups, and some substrates cannot be assumed to be true physiological substrates based only on their conversion rates (e.g., testosterone 6␤-hydroxylation for hepatic P450 3A4), in the absence of other evidence of function. Although extensive research efforts have been directed to elucidating the endogenous and exogenous functions of individual P450s, one-fourth of the human P450s still have not been assigned ...

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Section: Discussionmentioning

confidence: 99%

mRNA Distribution and Heterologous Expression of Orphan Cytochrome P450 20A1

Stark

Wu²,

Bartleson³

et al. 2008

Drug Metab Dispos

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“…In humans, P450 isozymes are expressed and active not only in liver, but also in extrahepatic tissues including the brain (Riedl et al, 1998;Hedlund et al, 2001;Strobel et al, 2001;Miksys et al, 2002). Cytochrome P450s belonging to the CYP1A, CYP2C, CYP2D, and CYP3A subfamilies have all been detected in human brain.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Individual Cytochrome P450 Isozymes to theO-Demethylation of the Psychotropic β-Carboline Alkaloids Harmaline and Harmine

Idle²,

Krausz

et al. 2003

J Pharmacol Exp Ther

113

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The psychotropic ␤-carboline alkaloids, showing high affinity for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline receptors and the stimulation of locus coeruleus neurons, are formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with aldehydes in both plants and mammals. Cytochromes P450 1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O-demethylation of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9 (16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of harmine (relative activities). The dehydrogenation/aromatization of harmaline to harmine was not carried out by aromatase (CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant cytochromes P450, or human liver microsomes (HLMs). Kinetic parameters were calculated for the O-demethylations mediated by each isozyme and by pooled HLMs. K cat (min Ϫ1 ) and K m (M) values for harmaline were: CYP1A1, 10. 8 and 11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19, 10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for harmine were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9, 11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and 7.4. Inhibition studies using monoclonal antibodies confirmed that CYP1A2 and CYP2D6 were the major isozymes contributing to both harmaline (20% and 50%, respectively) and harmine (20% and 30%) O-demethylations in pooled HLMs. The turnover numbers for CYP2D6 are among the highest ever reported for a CYP2D6 substrate. Finally, CYP2D6-transgenic mice were found to have increased harmaline and harmine O-demethylase activities as compared with wild-type mice. These findings suggest a role for polymorphic CYP2D6 in the pharmacology and toxicology of harmine and harmaline.The ␤-carboline alkaloids are present in plants and have been of interest due to their psychotropic properties (Picada et al., 1997). They may be formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with simple aldehydes or with pyruvic acid in mammals, including humans (Airaksinen and Kari, 1981;Melchior and Collins, 1982). Moreover, certain ␤-carbolines, such as pinoline, tryptoline, 6-hydroxy-tetrahydro-␤-carboline, harman, and norharman (Table 1), have been reported as normal constituents of human tissues and body fluids. Their levels in humans are usually elevated after drinking alcohol. The association of ␤-carbolines with alcohol dependence and brain damage has been suggested (Melchior and Collins, 1982;Collins, 2002).Endogenous and exogenous ␤-carboline alkaloids were reported to exert a wide spectrum of psychopharmacological and behavioral effects in the brain (Airaksinen and Kari, 1981). Most ␤-carbolines are strong reversible inhibitors of monoamine oxidase (MAO). Among them, harmaline and harmine (Table 1) exhibit the most potent inhibition toward purified MAO-A activity (Kim et al., 1997), and these are the principal active agents in Peganum harmala, a plant that has been used in traditional medicine for two millennia (Lamchou...

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“…The CYP2D6A mutant allele contains a deletion in exon 3, while the CYP2D6B mutant allele contains a G-to-A transition at the intron 3\ exon 4 junction. Polymorphisms in CYP2D6 can produce active protein products, which can exhibit alterations in catalytic function, protein stability or membrane integration (Tsuneoka et al 1993 ;Riedl et al 1998). CYP2D6B has been the most intensively studied mutant allele as it accounts for 75 % of poor metabolisers.…”

Section: Detoxification Enzymes and Pdmentioning

confidence: 99%

Genetics of Parkinsonism: a review

VAUGHAN¹,

DAVIS²,

WOOD³

2001

Annals of Human Genetics

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Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, low heritability in the general population and genetic heterogeneity. Mutations in a further gene, UCHL1, have been described in familial PD although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and illustrates how the existence of genetic factors has now become firmly established.

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P450 enzymes and Parkinson's disease: The story so far

Cited by 79 publications

References 68 publications

mRNA Distribution and Heterologous Expression of Orphan Cytochrome P450 20A1

mRNA Distribution and Heterologous Expression of Orphan Cytochrome P450 20A1

Contribution of Individual Cytochrome P450 Isozymes to theO-Demethylation of the Psychotropic β-Carboline Alkaloids Harmaline and Harmine

Genetics of Parkinsonism: a review

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