Pharmaceutical Plasticizers for Drug Delivery Systems

El-Gendy, Nashwa

doi:10.2174/156720112800234602

Cited by 12 publications

(8 citation statements)

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“…In addition to these well-known EDCs, there are many phthalate substitute plasticizers that have not been tested for endocrine disruption. For example, citrate esters, including TBC, ATBC, and triethyl citrate (TEC), represent a large group of plasticizers that have been approved by the FDA to be used in food packaging materials, vinyl toys, medical devices, cosmetics, and pharmaceutical drugs (53)(54)(55)(56). ATBC has recently been shown to activate PXR and induce PXR target gene expression (45).…”

Section: Discussionmentioning

confidence: 99%

Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

Sui

Helsley

Park

et al. 2015

Molecular Endocrinology

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Recent studies have associated endocrine-disrupting chemical (EDC) exposure with the increased risk of cardiovascular disease in humans, but the underlying mechanisms responsible for these associations remain elusive. Many EDCs have been implicated in activation of the nuclear receptor pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism in the liver and intestine. Here we report an important role of intestinal PXR in linking xenobiotic exposure and hyperlipidemia. We identified tributyl citrate (TBC), one of a large group of Food and Drug Administration-approved plasticizers for pharmaceutical or food applications, as a potent and selective PXR agonist. TBC efficiently activated PXR and induced PXR target gene expression in vitro and in vivo. Interestingly, TBC activated intestinal PXR but did not affect hepatic PXR activity. Exposure to TBC increased plasma total cholesterol and atherogenic low-density lipoprotein cholesterol levels in wild-type mice, but not in PXR-deficient mice. TBC-mediated PXR activation stimulated the expression of an essential cholesterol transporter, Niemann-Pick C1-like 1 (NPC1L1), in the intestine. Promoter analysis revealed a DR-4 type of PXR response element in the human NPC1L1 promoter, and TBC promoted PXR recruitment onto the NPC1L1 promoter. Consistently, TBC treatment significantly increased lipid uptake by human and murine intestinal cells and deficiency of PXR inhibited TBC-elicited lipid uptake. These findings provide critical mechanistic insight for understanding the impact of EDC-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating the adverse effects of EDCs on cardiovascular disease risk in humans.

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Section: Discussionmentioning

confidence: 99%

Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

Sui

Helsley

Park

et al. 2015

Molecular Endocrinology

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“…The United States Pharmacoepia deems both TEC and TBC appropriate to be used in pharmaceutical dosage forms [29]. They are used in gelatin capsules, enteric coatings on pills, and transdermal drug delivery patches [27, 28, 30]. They are also used in poly(vinyl chloride) and poly(vinyl acetate) components of medical devices, including tubing and films [31].…”

Section: Discussionmentioning

confidence: 99%

The effect of plasticizers on the erosion and mechanical properties of polymeric films

et al. 2013

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Cellulose acetate phthalate (CAP) and Pluronic F-127 combined together (70:30 wt:wt) create a rigid, surface eroding association polymer. To impart flexibility into the polymer system and allow for a drug delivery film that can contour to varying wound shapes, plasticizers were added. Triethyl citrate (TEC) or tributyl citrate (TBC) was combined with CAP and Pluronic F-127 at 0, 10, or 20 wt%. Mechanical analysis was performed on the films as they were prepared and following a 2 hour incubation in phosphate-buffered saline. Tensile tests showed that higher plasticizer content increased the % elongation but decreased the elastic modulus (E) and ultimate tensile strength (UTS). The effect TEC had on the % elongation was twice as much than that of TBC. After incubation, % elongation, E, and UTS all increased because plasticizer leached out of the films. MicroCT and SEM were performed on the samples both before and after incubation to determine how erosion and leaching of plasticizer affected the interior and exterior structure of the films. Porosity increased as plasticizer content increased, however, plasticizer content did not have a significant effect on the rate of erosion. The mechanical properties of CAP-Pluronic films can be adjusted by the type and amount of plasticizer added to the system and therefore can be tailored for different drug delivery applications.

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“…di-(2-ethylhexyl)phthalate, DEHP] on human health have attracted considerable attention and engendered controversy in the past few decades, partly due to their endocrine-disrupting properties. In addition to these well-known EDCs, there are many phthalate substitute plasticizers that have not been well studied for endocrine disruption [ 17 , 94–96 ]. For example, citrate esters, including TBC, acetyl tributyl citrate (ATBC), and triethyl citrate, represent a large group of plasticizers that have been approved by the FDA to be used in food packaging materials, vinyl toys, medical devices, cosmetics, and pharmaceutical drugs [ 94 , 95 , 97 , 98 ].…”

Section: Role Of Pxr In Mediating the Adverse Effects Of Edcs On Cvdmentioning

confidence: 99%

“…In addition to these well-known EDCs, there are many phthalate substitute plasticizers that have not been well studied for endocrine disruption [ 17 , 94–96 ]. For example, citrate esters, including TBC, acetyl tributyl citrate (ATBC), and triethyl citrate, represent a large group of plasticizers that have been approved by the FDA to be used in food packaging materials, vinyl toys, medical devices, cosmetics, and pharmaceutical drugs [ 94 , 95 , 97 , 98 ]. Several citrate esters including TBC and ATBC have been identified as potent and selective PXR agonists [ 76 , 99 ] ( Table 1 ).…”

Section: Role Of Pxr In Mediating the Adverse Effects Of Edcs On Cvdmentioning

confidence: 99%

Epigenetic impact of endocrine disrupting chemicals on lipid homeostasis and atherosclerosis: a pregnane X receptor-centric view

Helsley

Zhou

2017

Environmental Epigenetics

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Despite the major advances in developing diagnostic techniques and effective treatments, atherosclerotic cardiovascular disease (CVD) is still the leading cause of mortality and morbidity worldwide. While considerable progress has been achieved to identify gene variations and environmental factors that contribute to CVD, much less is known about the role of “gene–environment interactions” in predisposing individuals to CVD. Our chemical environment has significantly changed in the last few decades, and there are more than 100,000 synthetic chemicals in the market. Recent large-scale human population studies have associated exposure to certain chemicals including many endocrine disrupting chemicals (EDCs) with increased CVD risk, and animal studies have also confirmed that some EDCs can cause aberrant lipid homeostasis and increase atherosclerosis. However, the underlying mechanisms of how exposure to those EDCs influences CVD risk remain elusive. Numerous EDCs can activate the nuclear receptor pregnane X receptor (PXR) that functions as a xenobiotic sensor to regulate host xenobiotic metabolism. Recent studies have demonstrated the novel functions of PXR in lipid homeostasis and atherosclerosis. In addition to directly regulating transcription, PXR has been implicated in the epigenetic regulation of gene transcription. Exposure to many EDCs can also induce epigenetic modifications, but little is known about how the changes relate to the onset or progression of CVD. In this review, we will discuss recent research on PXR and EDCs in the context of CVD and propose that PXR may play a previously unrealized role in EDC-mediated epigenetic modifications that affect lipid homeostasis and atherosclerosis.

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Pharmaceutical Plasticizers for Drug Delivery Systems

Cited by 12 publications

References 0 publications

Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

The effect of plasticizers on the erosion and mechanical properties of polymeric films

Epigenetic impact of endocrine disrupting chemicals on lipid homeostasis and atherosclerosis: a pregnane X receptor-centric view

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