Mechanism of Action of Aminosalicylates

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Animation Description: This animation explains the mechanism of action of aminosalicylates used for the treatment of inflammatory bowel disease (IBD).

Aminosalicylates include sulfasalazine and 5-aminosalicylic acid (5-ASA).

Sulfasalazine, a sulfa drug, inhibits folic acid synthesis. As such, folic acid supplements should be taken with sulfasalazine to reduce the risk of neural tube defects.

Sulfasalazine exhibits anti-inflammatory properties when split by gut bacterium into its metabolites: sulfapyridine and 5-ASA (mesalamine).

The anti-inflammatory benefits of sulfasalazine, are chiefly derived from 5-ASA, which has fewer side effects than sulfapyridine. As such, administration of 5-ASA alone may be preferred over sulfasalazine.

5-ASA is poorly absorbed by the intestines and systemic circulation, thus most remains in the terminal ileum and colon or is passed in the stool. 5-ASA within the lumen primarily exhibits a topical effect on the colonic epithelium.

Absorbed 5-ASA is extensively metabolized to N-acetyl-5-ASA by N-acetyltransferase 1 (NAT1). N-acetyl-5-ASA then binds PPAR-gamma (peroxisome proliferator-activated receptor gamma) a nuclear hormone receptor.

Binding of N-acetyl-5-ASA induces the translocation of PPAR-gamma from the cytoplasm to the cell nucleus and a conformational change in PPAR-gamma.

This modification permits the recruitment of the co-activator, vitamin D3 receptor-interacting protein (DRIP), which interacts directly with PPAR-gamma.

Heterodimerization with the retinoid X receptor (RXR) occurs, resulting in formation of the PPAR-RXR complex, a transcriptional regulator.

The PPAR-RXR heterodimer controls transcription by binding a regulatory PPAR-gamma response element (PPRE) and modulating the expression of genes involved in the inflammation process.

PPAR-RXR downregulates the nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK) to reduce production of pro-inflammatory cytokines.

This complex also reduces COX-2 activity, leading to a reduction in prostaglandins involved in inflammation.

Novel agents with similar mechanisms to 5-ASA, but which target PPAR-gamma more efficiently and report a reduction of adverse events, are currently under investigation.

For example the compound, GED-0507-34, exhibits a 100- to 150-fold greater anti-inflammatory effect than 5-ASA.

A new generation of 5-ASA, balsalazide, is able to bypass the small intestine and release a high concentration of 5-ASA in the colon.

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