Progesterone Oxidation by Cytochrome P450 2D Isoforms in the Brain

Hiroi, Toyoko; Kishimoto, Wataru; Chow, T. L.; Imaoka, Shingi; Igarashi, Takashi; Funae, Yoshihiko

doi:10.1210/endo.142.9.8363

Cited by 69 publications

(14 citation statements)

References 47 publications

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“…The natural ligands of the CYP11B family are steroids, and steroids can be substrates for hepatic cytochromes that belong to the microsomal cytochrome P450 class. In CYP2C5 and CYP2D6 steroids are oxidised on the β-side of the steroid skeleton at carbon atoms close to C 11 and C 18 [ 50 ], and their crystal structures may possess the necessary interaction features for model construction. However, investigation of the crystal structure of CYP2D6 (PDB code: 2F9Q) raised doubt on the appropriateness for its use as a template structure.…”

Section: Methodsmentioning

confidence: 99%

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Roumen

Sanders

Pieterse

et al. 2007

J Comput Aided Mol Des

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Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11b-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat. The models were constructed based on the crystal structure of Pseudomonas Putida CYP101 and Oryctolagus Cuniculus CYP2C5. Small steric active site differences between the isoforms were found to be the most important determinants for the regioselective steroid synthesis. A possible explanation for these steric differences for the selective synthesis of aldosterone by CYP11B2 is presented. The activities of the known CYP11B inhibitors metyrapone, R-etomidate, R-fadrazole and S-fadrazole were determined using assays of V79MZ cells that express human CYP11B1 and CYP11B2, respectively. By investigating the inhibitors in the human CYP11B models using molecular docking and molecular dynamics simulations we were able to predict a similar trend in potency for the inhibitors as found in the in vitro assays. Importantly, based on the docking and dynamics simulations it is possible to understand the enantioselectivity of the human enzymes for the inhibitor fadrazole, the R-enantiomer being selective for CYP11B2 and the S-enantiomer being selective for CYP11B1.

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Section: Methodsmentioning

confidence: 99%

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Roumen

Sanders

Pieterse

et al. 2007

J Comput Aided Mol Des

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“…Propranolol 5-hydroxylation was catalyzed by rat CYP2D2 and CYP2D4 at low enzymatic activity [15]. The 7-hydroxylation of propranolol was catalyzed only by rat CYP2D2 [24]. After oral administration, propranolol kinetics depends on a number of factors associated with the drug (e.g.…”

Section: Introductionmentioning

confidence: 99%

Induction of Propranolol Metabolism by Ginkgo biloba Extract EGb 761 in Rats

Zhao¹,

Huang²,

Chen³

et al. 2006

CDM

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Ginkgo biloba is one of the most popular herbal medicines in the world, due to its purported pharmacological effects, including memory-enhancing, cognition-improving, and antiplatelet effects. When used in the elderly, Ginkgo has a high potential for interactions with cardiovascular drugs. This study aimed to investigate the effects of the standard Ginkgo biloba extract (EGB 761) treatment on the pharmacokinetics of propranolol and its metabolism to form Ndesisopropylpropranolol (NDP) in rats. We also examined the activity and expression of cytochrome P450 (CYP) 1A and other CYPs in rats treated with EGb 761 at 10 and 100 mg/kg/day for 10 days. A single oral dose of propranolol (10 mg/kg) was administered on day 11 and the concentrations of both propranolol and NDP were determined using validated liquid chromatography-mass spectrometry (LC-MS) methods. The levels of mRNA and protein of various CYPs were determined by RT-PCR and Western blotting analysis, respectively. Pretreatment of EGb 761 at 100 mg/kg, but not 10 mg/kg, for 10 days significantly reduced the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of propranolol, whereas those values of NDP were significantly increased. CYP1A1, 1A2, 2B1/2, and 3A1 activities and gene expression in the rat liver were significantly increased in a dose-dependent manner by pretreatment with EGb 761. The ex-vivo formation of NDP in liver microsomes from rats pretreated with EGb 761 was markedly enhanced. The formation of NDP from propranolol in liver microsomes was significantly inhibited by α-naphthoflavone (ANF, a selective CYP1A2 inhibitor), but not by quinidine (a CYP2D inhibitor). These results indicated that EGb 761 pretreatment decreased the plasma concentrations of propranolol by accelerated conversion of parental drug to NDP due to induction of CYP1A2. EGb 761 pretreatment also significantly induced CYP2B1/2 and CYP3A1, suggesting potential interactions with substrate drugs for these two enzymes. Further study is needed to explore the potential for gingko-drug interactions and the clinical impact.

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“…4 and Ref. 71) and recent reports of P450 2D6 binding and oxidation of steroids (53,(83)(84)(85) and drugs devoid of a basic nitrogen atom (e.g. spirosulfonamide).…”

Section: Basis Of Differences In Product Regioselectivity In Nadph-p4mentioning

confidence: 84%

Diversity in Mechanisms of Substrate Oxidation by Cytochrome P450 2D6

Hanna¹,

Krauser²,

Cai³

et al. 2001

Journal of Biological Chemistry

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Cytochrome P450 (P450) 2D6 was first identified as the polymorphic human debrisoquine hydroxylase and subsequently shown to catalyze the oxidation of a variety of drugs containing a basic nitrogen. Differences in the regioselectivity of oxidation products formed in systems containing NADPH-P450 reductase/NADPH and the model oxidant cumene hydroperoxide have been proposed by others to be due to an allosteric influence of the reductase on P450 2D6 (Modi, S., Gilham, D. E., Sutcliffe, M. J., Lian, L.-Y., Primrose, W. U., Wolf, C. R., and Roberts, G. C. K. (1997) Biochemistry 36, 4461-4470). We examined the differences in the formation of oxidation products of N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, metoprolol, and bufuralol between reductase-, cumene hydroperoxide-, and iodosylbenzene-supported systems. Catalytic regioselectivity was not influenced by the presence of the reductase in any of the systems supported by model oxidants, ruling out allosteric influences. The presence of the reductase had little effect on the affinity of P450 2D6 for any of these three substrates. The addition of the reaction remnants of the model oxidants (cumyl alcohol and iodobenzene) to the reductase-supported system did not affect reaction patterns, arguing against steric influences of these products on catalytic regioselectivity. Label from H 2 18 O was quantitatively incorporated into 1-hydroxybufuralol in the iodosylbenzene-but not in the reductase-or cumene hydroperoxide-supported reactions. We conclude that the P450 systems utilizing NADPH-P450 reductase, cumene hydroperoxide, and iodosylbenzene use similar but distinct chemical mechanisms. These differences are the basis for the variable product distributions, not an allosteric influence of the reductase. P4501 enzymes (also termed "heme-thiolate protein P450"; Ref. 1) are involved in the oxidations of many organic chemicals (2-4). The P450 enzymes are found in nearly all life forms, but there has been particular interest in the mammalian P450 enzymes that dominate the metabolism of drugs (5). P450s constitute an important target in pharmacogenomic efforts because variation among individual humans can have a major influence on the efficacy of drugs (6).P450 2D6 was first identified as the polymorphic enzyme involved in debrisoquine hydroxylation (7) and sparteine oxidation (8). This enzyme is involved in the metabolism of approximately one third of the drugs used today (5). P450 2D6 polymorphism is relatively well understood today (9 -11), and our own efforts have been directed to better understanding the biochemical basis of P450 2D6 activity. In our early research with purified P450 2D6 (12), the observation was made that most of the substrates of P450 2D6 contain a basic nitrogen atom, which is located ϳ5 Å away from the site of oxidation (13,14). This concept was developed with more detailed pharmacophore and homology models for P450 2D6 (15-18).A problem in modeling of P450 2D6 arose with the report of Modi et al. (19) that differences were observed between MPTP oxid...

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Progesterone Oxidation by Cytochrome P450 2D Isoforms in the Brain

Cited by 69 publications

References 47 publications

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Induction of Propranolol Metabolism by Ginkgo biloba Extract EGb 761 in Rats

Diversity in Mechanisms of Substrate Oxidation by Cytochrome P450 2D6

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