Mycophenolic acid as a latent agonist of PPARγ

Ubukata, Makoto; Takamori, Hitomi; Ohashi, Misaki; Mitsuhashi, Shinya; Yamashita, Kaoru; Asada, Tomohisa; Nakajima, Noriyuki; Matsuura, Nobuo; Tsuruga, Mie; Taki, Keiko; Magae, Junji

doi:10.1016/j.bmcl.2007.06.059

Cited by 12 publications

(5 citation statements)

References 14 publications

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“…One additional notable result was that the PPARγ activator pyridaben was a strong inhibitor of adipogenesis. While uncommon, this result is not unprecedented; mycophenolic acid is a known PPARγ activator that inhibits adipogenesis ( Ubukata et al 2007 ). There are two possible conclusions for the poor predictive power of the adipogenesis ToxPi.…”

Section: Discussionmentioning

confidence: 99%

On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens

Janesick

Dimastrogiovanni

Vanek

et al. 2016

Environ Health Perspect

118

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Background:In ToxCast™ Phase I, the U.S. EPA commissioned screening of 320 pesticides, herbicides, fungicides, and other chemicals in a series of high-throughput assays. The agency also developed a toxicological prioritization tool, ToxPi, to facilitate using ToxCast™ assays to predict biological function.Objectives:We asked whether top-scoring PPARγ activators identified in ToxCast™ Phase I were genuine PPARγ activators and inducers of adipogenesis. Next, we identified ToxCast™ assays that should predict adipogenesis, developed an adipogenesis ToxPi, and asked how well the ToxPi predicted adipogenic activity.Methods:We used transient transfection to test the ability of ToxCast™ chemicals to modulate PPARγ and RXRα, and differentiation assays employing 3T3-L1 preadipocytes and mouse bone marrow-derived mesenchymal stem cells (mBMSCs) to evaluate the adipogenic capacity of ToxCast™ chemicals.Results:Only 5/21 of the top scoring ToxCast™ PPARγ activators were activators in our assays, 3 were PPARγ antagonists, the remainder were inactive. The bona fide PPARγ activators we identified induced adipogenesis in 3T3-L1 cells and mBMSCs. Only 7 of the 17 chemicals predicted to be active by the ToxPi promoted adipogenesis, 1 inhibited adipogenesis, and 2 of the 7 predicted negatives were also adipogenic. Of these 9 adipogenic chemicals, 3 activated PPARγ, and 1 activated RXRα.Conclusions:ToxCast™ PPARγ and RXRα assays do not correlate well with laboratory measurements of PPARγ and RXRα activity. The adipogenesis ToxPi performed poorly, perhaps due to the performance of ToxCast™ assays. We observed a modest predictive value of ToxCast™ for PPARγ and RXRα activation and adipogenesis and it is likely that many obesogenic chemicals remain to be identified.Citation:Janesick AS, Dimastrogiovanni G, Vanek L, Boulos C, Chamorro-García R, Tang W, Blumberg B. 2016. On the utility of ToxCast™ and ToxPi as methods for identifying new obesogens. Environ Health Perspect 124:1214–1226; http://dx.doi.org/10.1289/ehp.1510352

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Section: Discussionmentioning

confidence: 99%

On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens

Janesick

Dimastrogiovanni

Vanek

et al. 2016

Environ Health Perspect

118

View full text Add to dashboard Cite

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“…Mycophenolic acid, discovered in 1896, attracted a lot of interest because of its variety of biological activities, such as anticancer, 12,13 antivirus, 14 peroxisome proliferator activated receptor-g agonism 15 and on account of one of its derivatives mycophenolate mofetil has been developed as an immunosuppressant. 3 Our findings provide two chemical entities of MPA family and their preliminary inhibitory activity to IMPDH.…”

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confidence: 99%

Two new members of mycophenolic acid family from Penicillium brevicompactum Dierckx

Zheng

Zhang

et al. 2009

J Antibiot

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“…Although this effect was attributed to the inhibition of IMPDH, another molecular target of 1 was found to be PPAR, and 1 was a latent agonist of this nuclear hormone receptor. 6) MPA has potential anti-cancer activity, and numerous studies have appeared in the literature. [7][8][9][10] Due to its apoptotic properties, 1 has entered phase I clinical trials in advanced multiple myeloma patients.…”

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confidence: 99%