Screening and detection of the in vitro agonistic activity of xenobiotics on the retinoic acid receptor

Kamata, Ryo; Shiraishi, Fujio; Nishikawa, J; Yonemoto, Junzo; Shiraishi, Hiroaki

doi:10.1016/j.tiv.2008.01.002

Cited by 54 publications

(25 citation statements)

References 30 publications

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“…However, results in this study do not completely exclude the possibility that 4-oxo-RAs are present in the rivers. That is, because SPE procedures applied in this study were different from those reported in the previous study Recent studies have also reported that synthetic compounds such as organochlorine pesticides, styrene dimers, monoalkylphenols and parabens show RAR agonistic activity in vitro (Nishikawa et al, 2003;Lemaire et al, 2005;Kamata et al, 2008). However, due to their low potencies, any contribution to the RARa agonistic activity of our samples should be negligible at normal environmental concentrations.…”

Section: Discussionmentioning

confidence: 72%

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan

et al. 2010

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RARa agonistic activityRiver Surface water Yeast two-hybrid assay a b s t r a c t This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) a in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan.To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARa agonist contamination in the river basins. RARa agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARa agonists are always present and widespread in the rivers. Comparative investigation of RARa and estrogen receptor a agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARa agonist contamination was entirely different from that of the estrogenic compound contamination.This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARa agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARa agonists in the rivers. Although a trial conducted to identify RARa agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARa agonistic activity were not RAs (natural RAR ligands) and 4-oxoRAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China.These findings suggest that there are unknown RARa agonists with high activity in the rivers. A v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / w a t r e s w a t e r r e s e a r c h 4 4 ( 2 0 1 0 ) 2 4 0 9 -2 4 1 80043-1354/$ -see front matter ª

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Section: Discussionmentioning

confidence: 72%

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan

et al. 2010

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“…However, TCMs usually comprise hundreds or thousands of components, only a few of which are responsible for the pharmaceutical and/or toxic effects. A large number of effective analysis techniques have been developed to determine the bioactive compounds of medicinal plants [3], including classic pharmacological approaches [4,5], molecular bio-chromatography [6,7], chromatographic fingerprinting [8,9], combinatorial chemistry [10], high-throughput screening [11], ultra-highthroughput screening [12], high-content screening [13] and DNA microarray technology [14]. Nevertheless, the large number of constituents in TCMs makes screening and analysis for bioactive compounds extremely difficult, even from well-documented formulations for specific diseases.…”

Section: Introductionmentioning

confidence: 99%

Screening vasoconstriction inhibitors from traditional Chinese medicines using a vascular smooth muscle/cell membrane chromatography‐offline‐liquid chromatography‐mass spectrometry

Yang

Wang

Zhang

et al. 2011

J of Separation Science

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We developed an analytical method for screening vasoconstriction inhibitors from traditional Chinese medicines (TCMs) by combining vascular smooth muscle/cell membrane chromatography (VSM/CMC) with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Primary cultured VSM cells from rat thoracic aortas were used for preparation of the stationary phase of the VSM/CMC column. Retention fractions from the VSM/CMC column were collected and then analyzed by LC-MS/MS under the optimized conditions offline. The suitability and reliability of the VSM/CMC-offline-LC-MS/MS method was assessed using nitrendipine and nifedipine as positive controls, and this method was then applied to screen vasodilator components from the extracts of Fructus Schisandrae Chinensis (FSC) and Fructus Schisandrae Sphenantherae (FSS). The major components from both species retained by VSM/CMC were identified as deoxyschizandrin (DSD) and schisantherin A (STA) by LC-MS/MS. Competition experiments indicated that DSD and nifedipine bound competitively to membrane receptors, while DSD and STA had partly overlapping binding sites on VSM-cell membranes. In vitro pharmacological trials confirmed that STA and DSD could dose-dependently relax the rat thoracic aortas pre-contracted by KCl. Our VSM/CMC-offline-LC-MS/MS method can be applied for screening vasoconstriction inhibitors from TCMs collected from FSC and FSS, and may be useful in the development of vasodilators from natural products.

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“…28,[41][42][43][44][45] Recent studies have also revealed that xenobiotic environmental pollutants can elicit the binding affinity to and the agonistic activity on RARs. Xenobiotic compounds including not only wellknown endocrine disrupting chemicals (EDCs) such as alkylphenols, [46][47][48] phthalate esters, 49) styrene dimers 48) and organochlorine pesticides 50) but also non-EDCs 51) have been proven to exhibit agonistic activity on one or several isotypes of RAR in vitro (Table 2). However, xenobiotic pollutants with agonistic activity at RARα are very limited as compared with those with RARβ or RARγ agonistic ability (Table 2).…”

Section: Natural and Xenobiotic Compounds That Act As Rar Agonistsmentioning

confidence: 99%

“…However, xenobiotic pollutants with agonistic activity at RARα are very limited as compared with those with RARβ or RARγ agonistic ability (Table 2). Kamata et al 48) evaluated the RARγ agonistic activity of 543 compounds including industrial chemicals, agrochemicals, natural compounds, medicines and cosmetic chemicals with a yeast two-hybrid assay, and revealed that 85 chemicals including 16 organochlorine pesticides, 14 styrene dimers, 9 alkylphenols and 6 parabens were active at RARγ (showing ≥ 20% of RARγ agonistic activity of 10 nM of atRA) at concentrations equal to 0.2-10 µM. Lemaire et al 50) also reported that organochlorine pesticides having teratogenic activities in animals (i.e., aldrin, chlordane, dieldrin, endrin and endosulfan) weakly activate RARβ and RARγ but do not activate RARα in a transactivation assay, and that among these five pesticides, endrin is the most effective at both RARβ and RARγ with 50% effective concentrations of 17.6 µM (6.7 mg/l) and 6.0 µM (2.3 mg/l), respectively.…”

Section: Natural and Xenobiotic Compounds That Act As Rar Agonistsmentioning

confidence: 99%

“…They investigated the occurrence of RARα agonistic activity in two widely separated sites in the U.S.A. (a permanent lake in Minnesota and a vernal pond a) RAR binding/agonistic potencies of xenobiotic compounds were calculated based on the lowest effective concentration in CoA-BAP (coactivator-bacterial alkaline phosphatase) assay 47,51) and also based on the 20% relative effective concentration in yeast two-hybrid assay. 48 • A permanent lake in Minnesota and a vernal pond in California, where malformed frogs were frequently observed in California) where deformed frogs had been frequently discovered. Consequently, a high response of RARα agonistic activity was detected commonly in both sites.…”

Section: Findings Of Rar Agonist Contamination In the Aquatic Environmentioning

confidence: 99%

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Disruption of Retinoic Acid Receptor Signaling by Environmental Pollutants

Inoue

Sei

Ike

2010

JOURNAL OF HEALTH SCIENCE

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Retinoic acid (RA) receptors (RARs) are nuclear receptors that play a critical role in regulating cellular proliferation, development and differentiation in vertebrates in response to endogenous RAs, i.e., all-trans RA and 9-cis RA. On the other hand, it has been well-known that both a deficiency and an excess of RA and related retinoids can cause a variety of teratogenic effects on developing embryos of vertebrates, which has been proven to be an RAR-mediated process. Therefore, the occurrence of xenobiotic environmental pollutants that interfere with RARs and disrupt the RAR signaling (i.e., show RAR agonistic or antagonistic effects) may pose a threat to the health of wild animals and humans. This review mainly focuses on RAR agonists. We summarize the RAR agonistic activity of natural and xenobiotic compounds determined using in vitro bioassay systems and present recent field research showing the occurrence of RAR agonist contamination in the aquatic environment in North America, China and Japan. Environmental pollution by RAR agonists is a new endocrine disruption issue discovered very recently, and relevant knowledge is very limited. Further research will be required to obtain accurate information to assess the possible risks of RAR agonists in the environment.

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Screening and detection of the in vitro agonistic activity of xenobiotics on the retinoic acid receptor

Cited by 54 publications

References 30 publications

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan

Screening vasoconstriction inhibitors from traditional Chinese medicines using a vascular smooth muscle/cell membrane chromatography‐offline‐liquid chromatography‐mass spectrometry

Disruption of Retinoic Acid Receptor Signaling by Environmental Pollutants

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