Comparative induction of CYP3A and CYP2B in rat liver by 3-benzoylpyridine and metyrapone

Murray, Michael T.; Sefton, Rachel M; Martini, Robert; Butler, Alison

doi:10.1016/s0009-2797(98)00017-9

Cited by 9 publications

(6 citation statements)

References 35 publications

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“…After a 30 min incubation on ice, the suspensions were centrifuged at 105,000 × g . The microsomal pellets were resuspended in 50 mM potassium phosphate buffer, pH 7.4, which contained 20% glycerol and 1 m M EDTA and frozen in liquid nitrogen for storage at −70° until required in experiments (Murray et al ., 1998).…”

Section: Methodssupporting

confidence: 91%

“…The microsomal pellet was resuspended in homogenisation buffer and treated with potassium ferricyanide (100 mm) to dissociate the ORPH MI-complex. After a 30 min incubation on ice, the suspensions were centrifuged at 105,000 Â g. The microsomal pellets were resuspended in 50 mM potassium phosphate buffer, pH 7.4, which contained 20% glycerol and 1 mm EDTA and frozen in liquid nitrogen for storage at À701 until required in experiments (Murray et al, 1998).…”

Section: Animal Treatmentsmentioning

confidence: 99%

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Upregulation of cytochromes P450 2B in rat liver by orphenadrine

Murray

Fiala-Beer

Sutton

2003

British J Pharmacology

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1 The alkylamine drug orphenadrine (ORPH) is an inducer and inhibitor of the microsomal cytochrome P450 (CYP) system in mammals. This study evaluated the selectivity of CYP induction by ORPH in rat liver. 2 Immunoblot analysis indicated that ORPH was a selective inducer of the phenobarbitone (PB)-inducible CYP2B in rat liver. CYP2B protein was increased to B14-fold of levels in untreated rat liver. By comparison PB increased CYP2B expression 40-fold. Corresponding increases in the activity of CYP2B-dependent androstenedione 16b-hydroxylation were measured in microsomes from ORPH and PB-induced rats. 3 Northern analysis indicated that CYP2B1/2 mRNA was increased in ORPH-induced rat liver. Consistent with this finding, ORPH was found to activate a PB-responsive enhancer module in constitutive androstane receptor (CAR)-transfected Hep G2 cells. 4 Other alkylamines like troleandomycin impair CYP turnover. We tested whether ORPH induction of CYP2B may include a post-translational component. In PB-pretreated animals ORPH administration delayed the loss of CYP2B after PB withdrawal, but no evidence for altered turnover was found. 5 These studies establish ORPH as a selective inducer of CYP2B in rat liver. Induction appears to be mediated pretranslationally by CAR activation of CYP2B gene transcription. Post-translational stabilisation by an ORPH metabolite does not elicit induction. Induction of CYP2B may influence pharmacokinetic interactions involving ORPH.

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Section: Methodssupporting

confidence: 91%

Section: Animal Treatmentsmentioning

confidence: 99%

Upregulation of cytochromes P450 2B in rat liver by orphenadrine

Murray

Fiala-Beer

Sutton

2003

British J Pharmacology

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“…Apart from CYP3A1, other CYP3A subfamily members, including CYP3A2, CYP3A9, CYP3A18 and CYP3A23, exist in rat liver [92][93][94][95]. CYP3A2, CYP3A9 and CYP3A23 have been shown to be markedly inducible by PB and many other inducers in rat liver [94,[96][97][98] and hence it would be of interest to investigate whether EGb 761 induces these CYP3A enzymes in the rat liver.…”

Section: Discussionmentioning

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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“…The supernatant was ultracentrifuged at 105 000 g for 60 min, followed by resuspension in buffer and resedimentation at 105 000 g for 30 min. The final microsomal pellets obtained were resuspended in 50 mM potassium phosphate buffer, pH 7.4, that contained 20% glycerol and 1 mM EDTA, frozen in liquid nitrogen and stored at -70 C until required (Murray et al 1999). Microsomal protein was determined by the method of Lowry et al (1951) using bovine serum albumin as standard.…”

Section: Animal Treatmentsmentioning

confidence: 99%

Mechanism-based inhibition of CYP activities in rat liver by fluoxetine and structurally similar alkylamines

Murray

Murray²

2003

Xenobiotica

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1. The inhibition of cytochrome P450 (CYP)-mediated substrate oxidations by alkylamine-based drugs was investigated in rat hepatic microsomes. The effects of pre-incubation of the drugs with NADPH-fortified microsomes on inhibition potency was evaluated in relation to the formation of metabolite intermediate (MI) complexes with CYP in vitro. 2. The selective serotonin-reuptake inhibitor fluoxetine (FLU) emerged as a potent and preferential inhibitor of CYP2C11 in rat liver microsomes. After FLU biotransformation in NADPH-supplemented microsomes, IC50 values of 2 and 1 microM were determined against CYP2C11-dependent testosterone 2alpha- and 16alpha-hydroxylation; in the absence of pre-incubation, the corresponding IC50 values were 47 and 39 microM. MI complexation of CYP appeared to contribute significantly to inhibition by FLU, as evidenced by the 21% decrease in apparent microsomal CYP content produced by 50 microM FLU in the presence of NADPH. 3. The secondary amines nisoxetine (NIS), and especially, desipramine (DES) and nortriptyline (NOR), also inhibited CYP2C11 and generated MI complexes with microsomal CYP. In contrast, with the exception of SKF-525-A, tertiary alkylamines (10 compounds) inhibited specific CYP activities but did not form MI complexes. Pre-incubation of these agents with NADPH-supplemented microsomes did not enhance inhibition of CYP activities, thus suggesting that formation of inhibitory metabolites was minimal for these compounds. 4. These findings implicate drug-mediated MI complexation of CYPs in the inhibition of hepatic biotransformation processes by secondary alkylamines. In contrast, tertiary amines did not generate significant quantities of CYP-MI complexes under the test conditions. Despite their diffusion from the CYP active site, inhibition produced by tertiary amines and stable metabolites of other drugs may be significant. However, such inhibition would be of shorter duration than that from MI complexation, which involves quasi-covalent binding to the haem and prevention of oxygen activation.

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Comparative induction of CYP3A and CYP2B in rat liver by 3-benzoylpyridine and metyrapone

Cited by 9 publications

References 35 publications

Upregulation of cytochromes P450 2B in rat liver by orphenadrine

Upregulation of cytochromes P450 2B in rat liver by orphenadrine

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

Mechanism-based inhibition of CYP activities in rat liver by fluoxetine and structurally similar alkylamines

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