Anatomical distribution of NADPH-cytochrome P450 reductase and cytochrome P4502D forms in rat brain: Effects of xenobiotics and sex steroids

Bergh, A F; Strobel, Henry W.

doi:10.1007/bf00250993

Cited by 8 publications

(3 citation statements)

References 22 publications

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“…However, the state of pregnancy can induce CYP2D, which suggests certain regulatory in¯uence of steroids. Bergh & Strobel (1996) and Baum & Strobel (1997) demonstrated regulation of expression of CYP2D mRNA in the rat brain with steroid hormones (an increase by testosterone and a decrease by progesterone). Therefore, a decrease in the level of cortisol by mirtazapine may have a connection with the observed increase in CYP2D activity in rats after chronic treatment with mirtazapine.…”

Section: Discussionmentioning

confidence: 99%

Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressants

Daniel

Wójcikowski

2002

Journal of Pharmacy and Pharmacology

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The aim of this study was to investigate the influence of tricyclic antidepressants (imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2D, measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg kg(-1) i.p.; desipramine, fluoxetine, sertraline 5 mg kg(-1) i.p.; mirtazapine 3 mg kg(-1) i.p.), in the absence of the antidepressants in-vitro. Antidepressants decreased the activity of the rat CYP2D by competitive inhibition of the enzyme, the potency of their inhibitory effect being as follows: clomipramine (K(i) = 14 microM) > sertraline approximate, equals fluoxetine (K(i) = 17 and 16 microM, respectively) > imipramine approximate, equals amitriptyline (K(i) = 26 and 25 microM, respectively) > desipramine (K(i) = 44 microM) > nefazodone (K(i) = 55 microM) > mirtazapine (K(i) = 107 microM). A one-day treatment with antidepressants caused a significant decrease in the CYP2D activity after imipramine, fluoxetine and sertraline. After prolonged administration of antidepressants, the decreased CYP2D activity produced by imipramine, fluoxetine and sertraline was still maintained. Moreover, amitriptyline and nefazodone significantly decreased, while mirtazapine increased the activity of the enzyme. Desipramine and clomipramine did not produce any effect when administered in-vivo. The obtained results indicate three different mechanisms of the antidepressants-CYP2D interaction: firstly, competitive inhibition of CYP2D shown in-vitro, the inhibitory effects of tricyclic antidepressants and SSRIs being stronger than those of novel drugs; secondly, in-vivo inhibition of CYP2D produced by both one-day and chronic treatment with tricyclic antidepressants (except for desipramine and clomipramine) and SSRIs, which suggests inactivation of the enzyme apoprotein by reactive metabolites; and thirdly, in-vivo inhibition by nefazodone and induction by mirtazapine of CYP2D produced only by chronic treatment with the drugs, which suggests their influence on the enzyme regulation.

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Section: Discussionmentioning

confidence: 99%

Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressants

Daniel

Wójcikowski

2002

Journal of Pharmacy and Pharmacology

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“…There have been very few studies on the presence and distribution of speci® c CYP2D subfamily member proteins and mRNA in rat brain regions, and these are confounded by the use of animals of both genders as it appears that CYP2D brain levels are in¯uenced by sex steroid hormones (Bergh and Strobel 1996). Immunodetection studies for speci® c isozymes are diae cult because the CYP2D subfamily members in the rat all have highly homologous mRNA and amino acid sequences.…”

Section: Presence Of Cyp2d Isozymes In Brainmentioning

confidence: 99%

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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“…In the brain, which lacks aldehyde oxidase activity, these intermediates may spontaneously oxidize to the pyridinium products 71 . Various members of the cytochrome P450 family of enzymes and coenzymes are known to be present in rodent ( − ) and human ( − ) brain. Consequently, it may be reasonable to speculate that appropriately functionalized piperidinyl derivatives may be converted to the corresponding pyridinium metabolites in the central nervous system.…”

Section: Piperidinols and Related Compoundsmentioning

confidence: 99%

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

Castagnoli

Rimoldi

Bloomquist

et al. 1997

Chem. Res. Toxicol.

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A major theme explored in this review is the MAO-and cytochrome P450-catalyzed alpha-carbon oxidations of selected cyclic tertiary amines to give iminium metabolites that undergo further chemical modifications to form known or potentially toxic products. The most dramatic illustration of this type of bioactivation process is the conversion of the parkinsonian-inducing neurotoxin MPTP (23) by brain MAO-B to the iminium (dihydropyridinium) metabolite 24 which is oxidized further to the pyridinium species MPP+ (25). The selective destruction of nigrostriatal neurons by MPP+ is dependent on a unique sequence of events (transport into the nerve terminals by the dopamine transporter, localization in the inner mitochondrial membrane by electromotive forces, and inhibition of complex I of the mitochondrial electron transport chain) that, fortunately, are unlikely to be encountered with many substances. A second example of a well-documented metabolic bioactivation sequence involves the highly toxic pyrrolizidine alkaloids (102). These compounds undergo cytochrome P450-catalyzed alpha-carbon oxidation which converts the 3-pyrrolinyl moiety present in the parent alkaloids into a pyrrolyl-containing metabolite (105). The presence of labile functional groups results in the spontaneous conversion of 105 to reactive electrophilic products (106 and 108) that undergo Michael addition reactions with nucleophiles on biomacromolecules leading to a variety of toxic outcomes. Less clearly defined are the potential contributions to neurodegenerative processes that may be mediated by low-level, long term exposure to less potent toxins. Examples of potential proneurotoxins are the endogenously formed tetrahydroisoquinolines (such as40-50) and tetrahydro-beta-carbolines (such as 54) that may be biotransformed to neurotoxic isoquinolinium (such as 51) and beta-carbolinium (such as 52) species in the brain. A similar argument can be made for 4-piperidinols (compounds that are at the same oxidation state as the tetrahydropyridines) which may be metabolized via iminium intermediates to amino enols that spontaneously convert to dihydropyridinium species and hence to pyridinium metabolites (67-->68-->69-->70-->71, Scheme 10). This type of reaction sequence has been well documented with the parkinsonian-inducing neuroleptic agent haloperidol (72) which is metabolized in humans, baboons, and rodents to the pyridinium species HPP+ (75), a potent inhibitor of mitochondrial respiration. Finally, an appreciation of the alpha-carbon oxidations of fully reduced azacycles such as (S)-nicotine (61) and phencyclidine (82) to chemically reactive metabolites that form covalent adducts with proteins, including the enzymes that are responsible for their formation, may prove of toxicological importance when attempting to account for the effects of chronic abuse of these potent drugs.1

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Anatomical distribution of NADPH-cytochrome P450 reductase and cytochrome P4502D forms in rat brain: Effects of xenobiotics and sex steroids

Cited by 8 publications

References 22 publications

Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressants

Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressants

Regional and cellular distribution of CYP2D subfamily members in rat brain

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

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