Drug delivery system for poorly water-soluble compounds using lipocalin-type prostaglandin D synthase

Fukuhara, Ayano; Nakajima, Hidemitsu; Miyamoto, Yuya; Inoue, Katsuaki; Kume, Satoshi; Lee, Young-Ho; Noda, Masanori; Uchiyama, Susumu; Shimamoto, Shigeru; Nishimura, Shigenori; Ohkubo, Tadayasu; Goto, Yuji; Takeuchi, Tadayoshi; Inui, Takashi

doi:10.1016/j.jconrel.2011.12.020

Cited by 19 publications

(33 citation statements)

References 49 publications

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“…Lipocalin family members often display promiscuous binding to other lipophilic compounds beside their endogenous ligands ( 24 ). Its broad specifi city in ligand binding suggests that L-PGDS could be exploited as a drug delivery system for lipophilic molecules ( 25 ).…”

Section: Data Collection and Processingmentioning

confidence: 99%

Structural and dynamic insights into substrate binding and catalysis of human lipocalin prostaglandin D synthase

Lim

Chen

Teo

et al. 2013

Journal of Lipid Research

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Section: Data Collection and Processingmentioning

confidence: 99%

Structural and dynamic insights into substrate binding and catalysis of human lipocalin prostaglandin D synthase

Lim

Chen

Teo

et al. 2013

Journal of Lipid Research

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“…It can act as a PGD2-synthesising enzyme and an extracellular transporter for lipophilic compounds [16]. Due to its ability to bind and carry lipophilic compounds, it was proposed as an efficient drug delivery vehicle to the brain dramatically increasing in-situ drugs' availability [17]. Exposure of the peripheral tissues such as gut, nasal mucosa and lungs to the lipophilic xenobiotics with potentially strong biological activities might result in binding of these compounds to the abundant lipophilic carriers with subsequent transfer and accumulation of those compounds to the remote tissues.…”

Section: Discussionmentioning

confidence: 99%

“…It is also abundantly expressed in peripheral tissues [15]. This protein exhibits a strong capacity to bind to a variety of lipophilic ligands [16] and was used as a drug delivery vehicle from gut to brain [17]. The 3D structure of human L-PGDS exhibits a single eight-stranded β-barrel with a deep calyx capable of simultaneous binding of several lipophilic or amphiphilic ligands [10] and Aβ peptides with nanomolar affinity [12] [11].…”

mentioning

confidence: 99%

“…However, the molecular mechanisms of these associations are not known. Given the fact that L-PGDS may contribute to controlling of Aβ aggregation [12] [11] and its ability to bind and transport a variety of drug-like small molecular ligands [26] [17], we hypothesize that these compounds might interfere with the Aβ homeostasis via their interaction with L-PGDS. Furthermore, some xenobiotics transported by L-PGDS may be capable of directly interacting with the Aβ peptides and modifying their morphology and cytotoxicity [27].…”

mentioning

confidence: 99%

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Xenobiotic compounds modulate cytotoxicity of Aβ amyloids and interact with neuroprotective chaperone L-PGDS

Low

Phillips

Pervushin

2020

Preprint

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A positive association of the exposure to different classes of xenobiotics such as commonly prescribed drugs and polycyclic aromatic hydrocarbons (PAH) typically those found in air pollution-related particulate matter with Alzheimer's disease (AD) may point to direct physical interaction of those compounds with the amyloid formation and clearance processes. In this study, for the first time, we provide evidence of such interactions for three representative compounds from prescription drugs and air pollution, e.g. anticholinergic drugs Chlorpheniramine, a common antihistamine, and Trazodone, an antidepressant as well as 9,10-PQ, a common PAH anthraquinone abundantly present in diesel exhaust and associated with AD. We demonstrate that these three compounds bind to the lipophilic compound carrier and neuroprotective amyloid beta (A) chaperone lipocalin-type prostaglandin D synthase (L-PGDS) with high affinity attenuating its neuroprotective chaperone function with Chlorpheniramine exhibiting markedly stronger inhibitory effects. We also show that these compounds directly interact with A(1-40) increasing the fibril's yield with altered fibril morphology and increased the cytotoxicity of the resulting fibrils. We propose that exposure to some xenobiotics in the peripheral tissues such as gut and lungs might result in the accumulation of these compounds in the brain facilitated by the carrier function of L-PGDS. This might lead to attenuation of its neuroprotective function and direct modification of 2 A amyloid morphology and cytotoxicity. This hypothesis might provide a mechanistic link between exposure to xenobiotic compounds and the increased risk of Alzheimer's disease.Graphical Abstract:

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“…To ensure a molecular interaction between serum albumin and the tested chemical, a fluorescence quenching assay was carried out according to a previous report with some modifications (Fukuhara et al, 2012). Each tested chemical and/or BSA were dissolved in 20 mM NaPB (pH 7.4) at a final concentration of 2 mM.…”

Section: Fluorescence Quenching Assaymentioning

confidence: 99%

Development of an albuminous reactive oxygen species assay for photosafety evaluation under experimental biomimetic conditions

Onoue

Kato

Yamada

2013

J of Applied Toxicology

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The generation of reactive oxygen species (ROS) from an ultraviolet (UV)-exposed chemical can be an experimental indicator of phototoxic potential. The aim of the present study was to develop a new ROS assay using serum albumin to provide photosafety assessment under experimental biomimetic conditions. To assess assay robustness, a validation study on an albuminous ROS (aROS) assay was conducted with a focus on intra- and inter-day precisions and Z'-factor reflecting both the assay signal-to-noise ratio and variation associated with signal measurements. In the aROS assay on quinine HCl (200 μM), a typical phototoxic drug, both intra- and inter-day precisions (coefficient of variation; CV) were found to be below 4%, and the Z'-factors for singlet oxygen and superoxide suggested a large separation band between samples and blank signals. To evaluate the prediction capacity, the aROS and ROS assays were applied to 21 phototoxins and 10 non-phototoxic chemicals. Upon aROS assay on these model chemicals, the individual specificity was 100%, and the positive and negative predictivities were found to be 100% and 81.8%, respectively. The aROS assay can be employed for poorly soluble chemicals for which the ROS assay is unavailable. Comparing the ROS assay data, there seemed to be a photochemical transition of some chemicals in albuminous solution. A molecular interaction between albumin and chemical was also assessed by UV and fluorescent spectroscopic analyses, and the results suggested the limited relationship between the albumin-chemical interaction and the photochemical change. The aROS assay may allow photosafety assessment of new drug entities with a wide range of applicability partly under experimental biomimetic conditions.

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Drug delivery system for poorly water-soluble compounds using lipocalin-type prostaglandin D synthase

Cited by 19 publications

References 49 publications

Structural and dynamic insights into substrate binding and catalysis of human lipocalin prostaglandin D synthase

Structural and dynamic insights into substrate binding and catalysis of human lipocalin prostaglandin D synthase

Xenobiotic compounds modulate cytotoxicity of Aβ amyloids and interact with neuroprotective chaperone L-PGDS

Development of an albuminous reactive oxygen species assay for photosafety evaluation under experimental biomimetic conditions

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