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Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.

ABSTRACT: BACKGROUND:Several microtubule targeting agents are capable of inducing CYP3A4 via activation of the pregnane X receptor (PXR; NR1I2). OBJECTIVE:To evaluate the CYP3A4 induction potential of vinblastine both clinically and in vitro and determine the involvement of the nuclear receptors NR1I2 and the constitutive androstane receptor (NR1I3). METHODS:Midazolam pharmacokinetics were evaluated in 6 patients who were enrolled in a Phase 1/2 study of infusional vinblastine given in combination with the ABCB1 (P-glycoprotein) antagonist valspodar (PSC 833) and received the CYP3A4 phenotyping probe midazolam on more than 1 occasion. Genotyping was conducted in CYP3A4, CYP3A5, and ABCB1 to rule out potential pharmacogenetic influences. Clinical data were followed-up by Western blotting and reporter assays in HepG2 and NIH3T3 cells treated with vinblastine over a dose range of 150-4800 ng/mL for 48 hours. RESULTS:In 6 patients with cancer, vinblastine increased the median (95% CI) clearance of the CYP3A4 phenotyping probe midazolam from 21.7 L/h (12.6 to 28.1) to 32.3 L/h (17.3 to 53.9) (p = 0.0156, Wilcoxon signed-rank test). No obvious effect of polymorphisms in CYP3A4, CYP3A5, and ABCB1 on midazolam clearance was observed. In vitro, vinblastine induced CYP3A4 protein. Furthermore, cell-based reporter gene assays using transiently transfected HepG2 and NIH3T3 cells indicated that vinblastine (150-4800 ng/mL) weakly activated human and mouse full-length NR1I2, but had no influence on NR1I3. CONCLUSIONS:Collectively, these findings suggest that vinblastine is able to induce CYP3A4, at least in part, via an NR1I2-dependent mechanism, and thus has the potential to facilitate its own elimination and cause interactions with other CYP3A4 substrates.

SUBMITTER: Smith NF

PROVIDER: S-EPMC3100585 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.

Smith Nicola F NF Mani Sridhar S Schuetz Erin G EG Yasuda Kazuto K Sissung Tristan M TM Bates Susan E SE Figg William D WD Sparreboom Alex A

The Annals of pharmacotherapy 20101019 11

<h4>Background</h4>Several microtubule targeting agents are capable of inducing CYP3A4 via activation of the pregnane X receptor (PXR; NR1I2).<h4>Objective</h4>To evaluate the CYP3A4 induction potential of vinblastine both clinically and in vitro and determine the involvement of the nuclear receptors NR1I2 and the constitutive androstane receptor (NR1I3).<h4>Methods</h4>Midazolam pharmacokinetics were evaluated in 6 patients who were enrolled in a Phase 1/2 study of infusional vinblastine given ...[more]

PMID: 20959500

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Project description:UNLABELLED:Herpesviruses, which include important pathogens, remodel the host cell nucleus to facilitate infection. This remodeling includes the formation of structures called replication compartments (RCs) in which herpesviruses replicate their DNA. During infection with the betaherpesvirus, human cytomegalovirus (HCMV), viral DNA synthesis occurs at the periphery of RCs within the nuclear interior, after which assembled capsids must reach the inner nuclear membrane (INM) for translocation to the cytoplasm (nuclear egress). The processes that facilitate movement of HCMV capsids to the INM during nuclear egress are unknown. Although an actin-based mechanism of alphaherpesvirus capsid trafficking to the INM has been proposed, it is controversial. Here, using a fluorescently-tagged, nucleus-localized actin-binding peptide, we show that HCMV, but not herpes simplex virus 1, strongly induced nuclear actin filaments (F-actin) in human fibroblasts. Based on studies using UV inactivation and inhibitors, this induction depended on viral gene expression. Interestingly, by 24 h postinfection, nuclear F-actin formed thicker structures that appeared by super-resolution microscopy to be bundles of filaments. Later in infection, nuclear F-actin primarily localized along the RC periphery and between the RC periphery and the nuclear rim. Importantly, a drug that depolymerized nuclear F-actin caused defects in production of infectious virus, capsid accumulation in the cytoplasm, and capsid localization near the nuclear rim, without decreasing capsid accumulation in the nucleus. Thus, our results suggest that for at least one herpesvirus, nuclear F-actin promotes capsid movement to the nuclear periphery and nuclear egress. We discuss our results in terms of competing models for these processes. IMPORTANCE:The mechanisms underlying herpesvirus nuclear egress have not been fully determined. In particular, how newly assembled capsids move to the inner nuclear membrane for envelopment is uncertain and controversial. In this study, we show that HCMV, an important human pathogen, induces actin filaments in the nuclei of infected cells and that an inhibitor of nuclear F-actin impairs nuclear egress and capsid localization toward the nuclear periphery. Herpesviruses are widespread pathogens that cause or contribute to an array of human diseases. A better understanding of how herpesvirus capsids traffic in the nucleus may uncover novel targets for antiviral intervention and elucidate aspects of the nuclear cytoskeleton, about which little is known.

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Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.

Publications

Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.

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