Effect of Hypoxia on Cytochrome P450 Activity and Expression

Fradette, Caroline; Souich, Patrick du

doi:10.2174/1389200043335577

Cited by 93 publications

(78 citation statements)

References 7 publications

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“…It showed that siHIF‐1α significantly decreased the HIF‐1α expression in hypoxic PC‐3 cells, and this effect was more obvious as for the c(RGDfK)‐modified targeted nanosystem. Consistent with previous reports,17, 36 HIF‐1α inhibition led to increased expressions of CYP1A1 and 2B6, which can be favorable for AQ4N activation. [[qv: 13a]]…”

Section: Resultssupporting

confidence: 91%

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A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

et al. 2018

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Vascular‐targeted photodynamic therapy (VTP) is a recently approved strategy for treating solid tumors. However, the exacerbated hypoxic stress makes tumor eradication challenging with such a single modality approach. Here, a new graphene oxide (GO)‐based nanosystem for rationally designed, interlocking trimodal cancer therapy that enables VTP using photosensitizer verteporfin (VP) (1) with codelivery of banoxantrone dihydrochloride (AQ4N) (2), a hypoxia‐activated prodrug (HAP), and HIF‐1α siRNA (siHIF‐1α) (3) is reported. The VTP‐induced aggravated hypoxia is highly favorable for AQ4N activation into AQ4 (a topoisomerase II inhibitor) for chemotherapy. However, the hypoxia‐induced HIF‐1α acts as a “hidden brake,” through downregulating CYP450 (the dominant HAP‐activating reductases), to substantially hinder AQ4N activation. siHIF‐1α is rationally adopted to suppress the HIF‐1α expression upon hypoxia and further enhance AQ4N activation. This trimodal nanosystem significantly delays the growth of PC‐3 tumors in vivo compared to the control nanoparticles carrying VP, AQ4N, or siHIF‐1α alone or their pairwise combinations. This multimodal nanoparticle design presents, the first example exploiting VTP to actively induce hypoxia for enhanced HAP activation. It is also revealed that HAP activation is still insufficient under hypoxia due to the hidden downregulation of the HAP‐activating reductases (CYP450), and this can be well overcome by GO nanoparticle‐mediated siHIF‐1α intervention.

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Section: Resultssupporting

confidence: 91%

“…[[qv: 13a]] Noticeably, HIF‐1α can also downregulate CYP450 via competitive binding with HIF‐1β against aryl hydrocarbon receptor (AhR) 17. In this manner, HIF‐1α actually acts as a “hidden brake” to substantially hinder AQ4N activation under hypoxia.…”

Section: Introductionmentioning

confidence: 99%

A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

et al. 2018

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“…with MDEC by microarray gene expression analysis. This could possibly be due to the hypoxic tumor microenvironment, where others have shown that cytochrome P450 enzyme expression and activity are down-regulated in hypoxic condition (27). Although more investigation is required to show that these genes are epigenetically silenced, our preliminary data suggest that cytochrome P450 enzyme expression could be epigenetically dysregulated in endothelial cells isolated from tumor microenvironment.…”

Section: Discussionmentioning

confidence: 67%

Epigenetic Silencing of CYP24 in Tumor-derived Endothelial Cells Contributes to Selective Growth Inhibition by Calcitriol

Chung

Karpf

Muindi

et al. 2007

Journal of Biological Chemistry

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Calcitriol (1,25-dihydroxycholecalciferol), the most active form of vitamin D, has selective anti-proliferative effects on tumor-derived endothelial cells (TDEC) compared with Matrigel-derived endothelial cells (MDEC). Although both cell types have an intact vitamin D receptor-signaling axis, this study demonstrates that upon treatment with calcitriol, 24-hydroxylase (CYP24) mRNA, protein and enzymatic activity were markedly induced in MDEC in a time-dependent manner but not in TDEC. Furthermore, treatment of MDEC with a CYP24 small interfering RNA restored sensitivity to calcitriol. To investigate the lack of CYP24 induction in TDEC, we examined methylation patterns in the promoter regions of the CYP24 gene in these two cell types. We identified two putative CpG island regions located at the 5 end. Using methylation-specific PCR and bisulfite sequencing, we determined that these CpG islands were hypermethylated in TDEC but not in MDEC. These data may explain the recruitment of vitamin D receptor to the promoter region in MDEC but not TDEC, as revealed by chromatin immunoprecipitation analyses. Treatment of TDEC with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine restored calcitriol-mediated induction of CYP24, which led to loss of sensitivity to calcitriol growth inhibitory effects. CYP24 promoter hypermethylation was also observed in endothelial cells isolated from other tumors but not in endothelial cells isolated from normal mouse tissues. These observations indicate that the methylation status of the CYP24 promoter differs in endothelial cells isolated from different microenvironments (tumor versus normal) and that methylation silencing of CYP24 contributes to selective calcitriol-mediated growth inhibition in endothelial cells.Although 1,25-dihydroxycholecalciferol (calcitriol), the most active metabolite of vitamin D 3 , is well known for its function in regulating calcium homeostasis and bone mineralization, it also plays a major role in modulating cellular proliferation and differentiation in a variety of cell types, including tumor cells (1). Calcitriol is growth inhibitory in several tumor models in vitro and in vivo including prostate, breast, and colon cancer and promotes cell differentiation, apoptosis, and cell cycle arrest (2-6).The effect of calcitriol in these tumors depends on the expression of the vitamin D receptor (VDR), 3 which upon binding to its ligand, acts as a transcription factor to regulate gene expression. In addition, the expression of the key enzyme of vitamin D catabolism, CYP24, also allows for a tight control of the effects of vitamin D in target tissues (7). Ligand-activated VDR induces expression of CYP24, which initiates inactivation and degradation of calcitriol by hydroxylation at C-24 (7). Overexpression of CYP24 has been documented in prostate, colon, and breast cancer during tumor progression (8), suggesting a mechanism of resistance of these tumor types to calcitriol treatment.Other than tumor cells, the effect of calcitriol on other cell types in the tumor...

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“…Due to the importance of adipocytes in energy regulations, current research is directed towards finding out signaling proteins impression involved in the adaptive strategy of fish adipocytes study to demonstrate its effect in adipocytes during pollutants induced hypoxia. Fradette and Souich [52] have reported the reduction in the expression of CYP1A2 in hypoxia induced animal models. Both HIF1α and CYP1A2 are biomarkers of environmental exposure to hypoxia and xenobiotics, act through the same aryl hydrocarbon receptor [21].…”

Section: Cyp1a2 (Ng/mg Protein)mentioning

confidence: 99%

Hif1α Mediated Ho-1 Expression in Fish Adipocytes: Role of Hypoxia In Ennore Estuary

Perumal¹,

Parasuraman²

2017

J Marine Sci Res Dev

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Heme oxygenase-1 (HO-1), an inducible stress protein; is involved in the regulation of adipogenesis, cellular bioenergetics and cytoprotective mechanism against hypoxia induced oxidative stress. Polluted aquatic environment leads to large oxygen fluctuations which may cause alteration in fish adaptation mechanism by HIF1α regulation. Environmental pollutants have a high tendency to accumulate, persist and bio-concentrate in adipocytes due to its lipophilic nature which ultimately causes adipocytes hypoxia that in turn affects metabolic energy balance. CYP1A2 and HO-1 are the chief detoxifying and cytoprotective enzymes involved in the oxidative metabolism of a wide variety of pollutants and its mediated cytotoxic products. The key role of hypoxia and its mediated signaling protein changes in fish adipocytes due to low dissolved oxygen in Ennore estuary was demonstrated in our previous work. Therefore, we analyzed the effect of pollutants induced hypoxia by assessing CD, HNE, TAC, G3PDH, ATP, HIF1α, HO-1 and CYP1A2 in fish adipocytes of control/unpolluted site and test/polluted site. Increase in CD, HNE, HIF1α, HO-1 along with a decrease in TAC, G3PDH, ATP and CYP1A2 observed in test adipocytes. From the results achieved, it shows that induction of HO-1 by HIF1α is crucial in maintaining the cell integrity to secure adipocytes and its maturation in the fish collected from the hypoxic environment. This study also highlights the role of HIF1α and HO-1 in regulating the expression of CYP1A2 during pollutants induced hypoxic condition.

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Effect of Hypoxia on Cytochrome P450 Activity and Expression

Cited by 93 publications

References 7 publications

A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

Epigenetic Silencing of CYP24 in Tumor-derived Endothelial Cells Contributes to Selective Growth Inhibition by Calcitriol

Hif1α Mediated Ho-1 Expression in Fish Adipocytes: Role of Hypoxia In Ennore Estuary

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