Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19

Agrawal, Vishal; Huang, Ningwu; Miller, Walter L.

doi:10.1097/fpc.0b013e32830054ac

Cited by 110 publications

(130 citation statements)

References 51 publications

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“…Electron transfer is the rate-limiting step for CYP-catalyzed oxidation-reduction reaction. The POR gene polymorphism (A503V) reduced the activity of CYP17, but had no effect on the activities of CYP1A2 and CYP2C19 (9). The experiments of transgenic mice have demonstrated that decreased activity of POR decreased the enzymatic activity of CYP (10).…”

Section: Introductionmentioning

confidence: 97%

Effects of genetic factors on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients

et al. 2014

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Abstract. The aim of the present study was to explore the effects of common genetic polymorphisms of cytochrome P450 (CYP)3A4, CYP3A5, cytochrome P450 oxidoreductase (POR) and multidrug resistance protein 1 (MDR1) on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients. The mild-to-moderate essential hypertension patients were recruited to complete the genotyping of CYP3A4, CYP3A5, POR and MDR1 by sequencing. After a 1-week placebo washout period, the subjects received 5 mg oral amlodipine daily for 4 weeks. Serial blood samples were collected prior to the last dosing, and 2, 6 and 24 h post-dosing. Blood pressures were measured prior and subsequent to dosing, and the demographical data were also collected. The blood samples were collected for laboratory testing. The plasma concentrations of amlodipine were determined by high-performance liquid chromatography/tandem mass spectrometry. A total of 60 patients, including 31 males and 29 females, completed the 4-week treatment. The plasma concentration of amlodipine in females at each time point was significantly higher compared to males (P<0.05). However, no significant gender differences existed in antihypertensive efficacy. The genetic polymorphisms of MDR1 C3435T had a certain impact on the plasma concentration of amlodipine, but did not affect its antihypertensive efficacy (P>0.05). The genetic polymorphisms of CYP3A4*1G, CYP3A5*3 and POR A503V showed no impact on plasma concentration and efficacy of amlodipine (P>0.05). Gender and MDR1 gene polymorphism may affect the plasma concentration of amlodipine in hypertensive patients. However, there was no impact on the efficacy of amlodipine.

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Section: Introductionmentioning

confidence: 97%

Effects of genetic factors on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients

et al. 2014

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“…The majority of these ABS-related POR mutations cause a reduction in CYPOR activity, such as Y181D, involved in FMN binding (Arlt et al, 2004;Huang et al, 2005;Marohnic et al, 2010), Y459H and V492E, involved in FAD binding (Marohnic et al, 2006;Kranendonk et al, 2008), and G539R, positioned in the NADPH binding domain (Huang et al, 2005). Of interest, some mutant proteins such as variant Q153R were reported to support increased P450 activity, compared with the wild-type enzyme (Agrawal et al, 2008Flück et al, 2010;Sandee et al, 2010). Variant A287P has been described as having differential behavior with different P450s (Fukami et al, 2005;Dhir et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Although the majority of studies on these CYPOR variants were initially focused on steroidogenesis, studies of our group (Kranendonk et al, 2008;Marohnic et al, 2010) and of others (Agrawal et al, 2008;Hart et al, 2008;Gomes et al, 2009) have attempted to evaluate the effects of these CYPOR variants on drug-metabolizing P450s. Two recent studies Flück et al, 2010) described the effect of ABS-related CYPOR variants on the major drug-metabolizing enzyme in humans, CYP3A4, which together with CYP3A5 is estimated to be involved in the metabolism of more than 50% of currently prescribed drugs (Guengerich, 2005).…”

Section: Introductionmentioning

confidence: 99%

Altered Human CYP3A4 Activity Caused by Antley-Bixler Syndrome-Related Variants of NADPH-Cytochrome P450 Oxidoreductase Measured in a Robust In Vitro System

Moutinho¹,

Marohnic²,

Panda³

et al. 2012

Drug Metab Dispos

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ABSTRACT:NADPH-cytochrome P450 oxidoreductase (CYPOR) variants have been described in patients with perturbed steroidogenesis and sexual differentiation, related to Antley-Bixler syndrome (ABS). It is important to determine the effect of these variants on CYP3A4, the major drug-metabolizing cytochrome P450 (P450) in humans. In this study, 12 CYPOR_ABS variants were separately coexpressed with CYP3A4 in a robust in vitro system to evaluate the effects of these variants on CYP3A4 activity in a milieu that recapitulates the stoichiometry of the mammalian systems.

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“…Likewise, CYP1A2 and CYP2C19 activities were not supported by Y181D (Agrawal et al, 2008). Shen et al (1989) previously characterized the orthologous Y178D variant of rat liver CYPOR using a bacterially expressed construct.…”

mentioning

confidence: 99%

Human Cytochrome P450 Oxidoreductase Deficiency Caused by the Y181D Mutation: Molecular Consequences and Rescue of Defect

Marohnic

Panda²,

McCammon

et al. 2009

Drug Metab Dispos

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Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19

Cited by 110 publications

References 51 publications

Effects of genetic factors on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients

Effects of genetic factors on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients

Altered Human CYP3A4 Activity Caused by Antley-Bixler Syndrome-Related Variants of NADPH-Cytochrome P450 Oxidoreductase Measured in a Robust In Vitro System

Human Cytochrome P450 Oxidoreductase Deficiency Caused by the Y181D Mutation: Molecular Consequences and Rescue of Defect

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