Expression and localisation of CYP2D enzymes in rat basal ganglia

Riedl, Andrew G.; Watts, Paul M.; Edwards, Robert J.; Schulz-Utermoehl, Timothy; Boobis, Alan R.; Jenner, Peter; Marsden, C. D.

doi:10.1016/s0006-8993(99)01113-0

Cited by 22 publications

(21 citation statements)

References 54 publications

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“…CYP2D is expressed in the pigmented neurons of rat substantia nigra (Riedl et al, 1996(Riedl et al, , 1999, and is co-localized with tyrosine hydroxylase (Watts et al, 1998) and the dopamine transporter (Tyndale et al, 1991). The expression of CYP2D in the substantia nigra, in cells that degenerate in PD, indicates that the enzyme is ideally situated to inactivate PD-causing neurotoxins.…”

Section: Discussionmentioning

confidence: 99%

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

et al. 2008

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Cytochrome P450 (CYP) 2D6, an enzyme found in the liver and the brain, is involved in the metabolism of numerous centrally acting drugs (e.g. antidepressants, neuroleptics, opiates), endogenous neurochemicals (e.g. catecholamines) and in the inactivation of neurotoxins (e.g. pesticides, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)). Although CYP2D6 is essentially an uninducible enzyme in the liver, we show that smokers have higher CYP2D6 in the brain, especially in the basal ganglia. In order to determine whether nicotine, a component of cigarette smoke, could increase brain CYP2D, African Green monkeys were treated chronically with nicotine (0.05 mg/kg for 2 days, then 0.15 mg/kg for 2 days followed by 0.3 mg/kg for 18 days s.c., b.i.d.). Monkeys treated with nicotine showed significant induction of CYP2D in brain when compared to saline-treated animals as detected by western blotting and immunocytochemistry. No changes in liver CYP2D were observed in nicotine-treated monkeys. Induction was observed in various brain regions including those affected in Parkinson's disease (PD) such as substantia nigra (3-fold, p = 0.01), putamen (2.1-fold, p = 0.001) and brainstem (2.4-fold, p = 0.001), with the caudate nucleus approaching significance (1.6-fold, p = 0.07).Immunocytochemistry revealed that the expression of CYP2D in both saline-and nicotine-treated monkeys is cell-specific particularly in the cerebellum, frontal cortex and hippocampus. These results suggest that monkey brain expresses CYP2D, which is induced in specific cells and brain regions upon chronic nicotine treatment. Smokers, or those using nicotine treatment, may have higher levels of brain CYP2D6 that may result in altered localized CNS drug metabolism and inactivation of neurotoxins.

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Section: Discussionmentioning

confidence: 99%

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

et al. 2008

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“…drugs, carcinogens) compounds (reviewed by Parkinson 1996). The liver is the major site of CYP-mediated xenobiotic metabolism, but these enzymes are also expressed in extrahepatic tissues such as the gastrointestinal tract, colon, lung, kidney, skin (reviewed by Krishna and Klotz 1994), nasal epithelium (Hadley and Dahl 1982), placenta (Pasanen and Pelkonen 1994), breast (Warner et al 1997) and the brain (Tyndale et al 1991, Warner et al 1997, Riedl et al 1999.…”

Section: Introductionmentioning

confidence: 99%

“…The overall metabolic capacities of these enzymes are low in the whole brain, but recent immunocytochemical investigations show that CYP are unevenly distributed across brain regions, and that diå erent isozymes are localized in discrete neurones and}or glial elements (Ghersi-Egea et al 1993, Norris et al 1996, Riedl et al 1999, as well as in the endothelium of the blood brain barrier (Ghersi-Egea et al 1994). The activity of a speci® c CYP isozyme may therefore be relatively high in one region, or even one cell type, while absent in another.…”

Section: Introductionmentioning

confidence: 99%

“…CYP2D6 is also present in human brain (Tyndale et al 1991, Bhamre et al 1993, Gilham 1997, and CYP2D6 has been characterized in canine and human brain using binding studies (Niznik et al 1990, Allard et al 1994. CYP2D1 catalytic activity (Jolivalt et al 1995, Laurenzana and Owens 1997, Tyndale et al 1999) and CYP2D immunoreactivity have been shown in rat brain (Norris et al 1996, Riedl et al 1999. The mRNA for CYP2D4 and for CYP2D1 and}or 5 have been isolated from rat brain, with that for CYP2D4 being the most abundant (Komori 1993, Wyss et al 1995.…”

Section: Introductionmentioning

confidence: 99%

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Regional and cellular distribution of CYP2D subfamily members in rat brain

et al. 2000

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1. Human CYP2D6 is present in brain, metabolizes many drugs and has been implicated in Parkinson's and Alzheimer's diseases and some cancers. It is still unclear which of the six known rat CYP2D subfamily members is/are homologous to human CYP2D6. 2. In this study, RT-PCR, Southern and Western blotting and immunohistochemical techniques were used to study the distribution of CYP2D subfamily member mRNA and proteins across 10 rat brain regions. CYP2D subfamily mRNA and protein levels were correlated with brain dextromethorphan O-demethylation (DOD), a measure of human CYP2D6 and rat CYP2D1 activities. 3. The data showed a strong relationship between CYP2D1 and CYP2D1-18 with brain DOD activity. In addition, it was shown that CYP2D proteins are present in brain mitochondrial as well as microsomal membranes. CYP2D subfamily member mRNA and proteins varied across brain regions and were highly concentrated in specific cell types. 4. These data strongly suggest that CYP2D1 and not CYP2D5 mediates DOD activity in rat brain, and may be the rat homologue of human CYP2D6. The highly localized nature of CYP2D indicates that in specific neurones enzyme levels may approach hepatic levels and, hence, contribute to local alterations in brain drug metabolism.

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“…Antibodies produced in this way have been used extensively in Western blotting and immunohistochemistry studies, and the results have provided information on the expression and locations of many P450 proteins in liver, lung, intestine, and brain (Debri et al, 1995;Riedl et al, 1996Riedl et al, , 1999Anttila et al, 1997;Raunio et al, 1999;Piipari et al, 2000).…”

Section: Edwards Et Almentioning

confidence: 99%

A Strategy for Investigating the Cyp Superfamily Using Targeted Antibodies Is a Paradigm for Functional Genomic Studies

Edwards

Boobis²,

Davies³

2003

Drug Metabolism and Disposition

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:In this review we describe the use of targeted antibodies developed to facilitate studies on the expression of P450 proteins. The challenge of producing specific antibodies that distinguish between often highly related P450 proteins has led to the development of methods of antibody production to meet this need. Targeting antibodies toward the C terminus of P450 proteins has been found to be a particularly successful approach that is both rapid and efficient at producing specifically binding antibodies. Recent advances in genomic sequencing and proteomics now allow ready identification of expressed proteins. The levels and distributions of these proteins may be determined using antibody-based methods. However, for each protein to be studied, a unique antibody will be required. Consequently, some means of producing large numbers of well defined antibodies is needed. In this context, the potential of extending the approach used to produce specific antibodies against P450 proteins to the wider field of functional genomics is discussed.

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Expression and localisation of CYP2D enzymes in rat basal ganglia

Cited by 22 publications

References 54 publications

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

Regional and cellular distribution of CYP2D subfamily members in rat brain

A Strategy for Investigating the Cyp Superfamily Using Targeted Antibodies Is a Paradigm for Functional Genomic Studies

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