Modulation of MDR1 and CYP3A Expression by Dexamethasone: Evidence for an Inverse Regulation in Adrenals

Sérée, Eric; Villard, Pierre-Henri; Hevér, Anikó; Guigal, Nolwen; Puyoou, F.; Charvet, Benjamin; Point-Scomma, H.; Lechevalier, E.; Lacarelle, Bruno; Barra, Yves

doi:10.1006/bbrc.1998.9662

Cited by 47 publications

(6 citation statements)

References 19 publications

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“…There is precedence for the former phenomenon. It has been shown that during chronic administration, various drugs and steroid hormones lose efficacy by inducing the expression of efflux transformers and cytochrome P450 [26],[27],[28]. However, we did not observe a measurable decrease in brain quinacrine levels during the course of treatment ( Fig.…”

Section: Discussionmentioning

confidence: 50%

Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions

et al. 2009

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Quinacrine is a potent antiprion compound in cell culture models of prion disease but has failed to show efficacy in animal bioassays and human clinical trials. Previous studies demonstrated that quinacrine inefficiently penetrates the blood-brain barrier (BBB), which could contribute to its lack of efficacy in vivo. As quinacrine is known to be a substrate for P-glycoprotein multi-drug resistance (MDR) transporters, we circumvented its poor BBB permeability by utilizing MDR0/0 mice that are deficient in mdr1a and mdr1b genes. Mice treated with 40 mg/kg/day of quinacrine accumulated up to 100 µM of quinacrine in their brains without acute toxicity. PrPSc levels in the brains of prion-inoculated MDR0/0 mice diminished upon the initiation of quinacrine treatment. However, this reduction was transient and PrPSc levels recovered despite the continuous administration of quinacrine. Treatment with quinacrine did not prolong the survival times of prion-inoculated, wild-type or MDR0/0 mice compared to untreated mice. A similar phenomenon was observed in cultured differentiated prion-infected neuroblastoma cells: PrPSc levels initially decreased after quinacrine treatment then rapidly recovered after 3 d of continuous treatment. Biochemical characterization of PrPSc that persisted in the brains of quinacrine-treated mice had a lower conformational stability and different immunoaffinities compared to that found in the brains of untreated controls. These physical properties were not maintained upon passage in MDR0/0 mice. From these data, we propose that quinacrine eliminates a specific subset of PrPSc conformers, resulting in the survival of drug-resistant prion conformations. Transient accumulation of this drug-resistant prion population provides a possible explanation for the lack of in vivo efficacy of quinacrine and other antiprion drugs.

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Section: Discussionmentioning

confidence: 50%

Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions

et al. 2009

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“…This hypothesis is supported by the report of Altuvia et al (1993), who observed that an increase in the steroid biosynthesis, induced by ACTH, resulted in an increase in the level of expression of mdr1 in a murine adrenal gland cell line. In line with this finding, Sérée et al (1998) observed that the inhibitory effect of dexamethasone on adrenocorticotropin hormone (ACTH) production can explain the decreased mdr1 expression. The rare expression of mdr1 during estrus and diestrus would be mostly related to its role as an adjuvant to mdr3 in detoxification rather than in hormone secretion.…”

Section: Discussionmentioning

confidence: 57%

Expression of mdr isoforms in mice during estrous cycle and under hormone stimulation

et al. 2006

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The multidrug resistance (MDR) phenotype is associated with the expression of P-glycoprotein (Pgp), coded by the multigenic mdr family. Mice present the isoforms mdr1 and mdr3, which are responsible for multidrug resistance, and mdr2, that is involved in the transport of phospholipids. mdr1 expression has more recently been associated also with the secretion of steroid hormones. This work presents an RT-PCR analysis of the expression of mdr isoforms, in several organs of mice during different phases of the estrous cycle. Additionally, females were ovariectomized, submitted to different hormone treatments, and their uterus was analyzed for the expression of mdr isoforms. The results show that in the adrenal gland and ovaries mdr1 is the main isoform during proestrus, and that progesterone or a combination of progesterone and estrogen induce the expression of all mdr isoforms in the uterus of ovariectomized females. We suggest that the functions of mdr1 and mdr3 are overlapping, that mdr3 may be the more efficient isoform in the detoxification function, and that mdr1 may be more closely related to the secretion of steroid hormones.

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“…Many studies showed that CYP activity can reflect the presence of environmental pollutants [ 29 ]. Alterations in CYP expression or enzymic activity in various organisms by many environmental contaminations have been reported; for example, heavy metals [ 30 , 31 ], 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [ 32 , 33 ], and dexamethasone [ 34 ]. It was reported that Microcystis aeruginosa 7820 decreased the levels of cytochrome b5 and cytochrome P450 in mouse [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Alteration in the Expression of Cytochrome P450s (CYP1A1, CYP2E1, and CYP3A11) in the Liver of Mouse Induced by Microcystin-LR

Zhang

Liu

2015

Toxins

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Microcystins (MCs) are cyclic heptapeptide toxins and can accumulate in the liver. Cytochrome P450s (CYPs) play an important role in the biotransformation of endogenous substances and xenobiotics in animals. It is unclear if the CYPs are affected by MCs exposure. The objective of this study was to evaluate the effects of microcystin-LR (MCLR) on cytochrome P450 isozymes (CYP1A1, CYP2E1, and CYP3A11) at mRNA level, protein content, and enzyme activity in the liver of mice the received daily, intraperitoneally, 2, 4, and 8 µg/kg body weight of MCLR for seven days. The result showed that MCLR significantly decreased ethoxyresorufin-O-deethylase (EROD) (CYP1A1) and erythromycin N-demthylase (ERND) (CYP3A11) activities and increased aniline hydroxylase (ANH) activity (CYP2E1) in the liver of mice during the period of exposure. Our findings suggest that MCLR exposure may disrupt the function of CYPs in liver, which may be partly attributed to the toxicity of MCLR in mice.

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Modulation of MDR1 and CYP3A Expression by Dexamethasone: Evidence for an Inverse Regulation in Adrenals

Cited by 47 publications

References 19 publications

Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions

Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions

Expression of mdr isoforms in mice during estrous cycle and under hormone stimulation

Alteration in the Expression of Cytochrome P450s (CYP1A1, CYP2E1, and CYP3A11) in the Liver of Mouse Induced by Microcystin-LR

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