Home
Resources
Publications
4-Methylumbelliferyl Glucuronide Contributes to Hyaluronan Synthesis Inhibition

4-Methylumbelliferyl Glucuronide Contributes to Hyaluronan Synthesis Inhibition

Nadine Nagy, Irina Gurevich, Hedwich F Kuipers, Shannon M Ruppert, Payton L Marshall, Bryan J Xie, Wenchao Sun, Andrey V Malkovskiy, Jayakumar Rajadas, Maria Grandoch, Jens W Fischer, Adam R Frymoyer, Gernot Kaber, etc.

J Biol Chem. 2019 May 10;294(19):7864-7877.

PMID: 30914479

Abstract:

4-Methylumbelliferone (4-MU) inhibits hyaluronan (HA) synthesis and is an approved drug used for managing biliary spasm. However, rapid and efficient glucuronidation is thought to limit its utility for systemically inhibiting HA synthesis. In particular, 4-MU in mice has a short half-life, causing most of the drug to be present as the metabolite 4-methylumbelliferyl glucuronide (4-MUG), which makes it remarkable that 4-MU is effective at all. We report here that 4-MUG contributes to HA synthesis inhibition. We observed that oral administration of 4-MUG to mice inhibits HA synthesis, promotes FoxP3+ regulatory T-cell expansion, and prevents autoimmune diabetes. Mice fed either 4-MUG or 4-MU had equivalent 4-MU:4-MUG ratios in serum, liver, and pancreas, indicating that 4-MU and 4-MUG reach an equilibrium in these tissues. LC-tandem MS experiments revealed that 4-MUG is hydrolyzed to 4-MU in serum, thereby greatly increasing the effective bioavailability of 4-MU. Moreover, using intravital 2-photon microscopy, we found that 4-MUG (a nonfluorescent molecule) undergoes conversion into 4-MU (a fluorescent molecule) and that 4-MU is extensively tissue bound in the liver, fat, muscle, and pancreas of treated mice. 4-MUG also suppressed HA synthesis independently of its conversion into 4-MU and without depletion of the HA precursor UDP-glucuronic acid (GlcUA). Together, these results indicate that 4-MUG both directly and indirectly inhibits HA synthesis and that the effective bioavailability of 4-MU is higher than previously thought. These findings greatly alter the experimental and therapeutic possibilities for HA synthesis inhibition.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP101702	4,4'-Dimethoxydiphenylamine		101-70-2	Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: