tbResList Print — PB Phenylbutyrate

Description: <b>Used</b> to treat urea cycle disorders<br>
Sodium phenylbutyrate helps remove ammonia from the body.<br>
-Phenyl-butyrate (PB)4 is an aromatic fatty acid that is converted in vivo to phenylacetate (PA) by β-oxidation in liver and kidney mitochondria.<br>
-In human body, phenylbutyrate is oxidized to phenylacetate, which is in turn conjugated with glutamine and eliminated in urine as phenylacetylglutamine, thereby mediating elimination of waste nitrogen<br>
-Phenylbutyrate is one of the first drugs encountered in cancer therapy as a histone deacetylase inhibitor (HDACI) (relatively weak compared to vorinostat (SAHA), romidepsin, etc.).<br>
-Butyric acid is one of the short-chain fatty acids produced by the gut microbiota through the fermentation of dietary fiber. Butyrate is primarily recognized for its beneficial effects in the colon and is tightly linked to gut health. <br>
-Phenylbutyrate is a derivative of butyrate that has been chemically modified by the addition of a phenyl group. This structural change increases its lipophilicity (fat solubility) and alters its metabolic fate and biological activity. This allows it to be used as a systemic drug, in contrast to the locally produced butyrate in the gut, which is rapidly metabolized by colonocytes<br>
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Pathways:<br>
-Histone deacetylase (HDAC) inhibitor<br>
-ER stress inhibitor (at least in normal cell)<br>
-Can act as a chemical chaperone, helping to reduce ER stress by facilitating proper protein folding.<br>
-Modulation of NF-κB Signaling<br>
-Changes in pathways such as PI3K/Akt/mTOR and MAPK.<br>
-Some preclinical investigations have reported that treatment with phenylbutyrate leads to mitochondrial dysfunction and endoplasmic reticulum (ER) stress, both of which can result in an increase of ROS within cancer cells. <br>
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Note: Sodium butyrate (NaBu) vs Sodium phenylbutyrate<br>
-Sodium butyrate is primarily a research tool with limited clinical application, whereas phenylbutyrate is used clinically<br>
-Phenylbutyrate typically exhibits improved pharmacokinetics and is more amenable to systemic use compared to sodium butyrate.<br>
-Both compounds act as HDAC inhibitors, phenylbutyrate additionally modulates ER stress and mitochondrial function, leading to potentially greater ROS production in certain cancer cells.<br>
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<!-- Phenylbutyrate (PB) — Time-Scale Flagged Pathway Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Context</th>
<th>Normal Tissue Context</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes</th>
</tr>

<tr>
<td>1</td>
<td>Histone Deacetylase (HDAC) inhibition</td>
<td>Histone acetylation ↑; p21 ↑; differentiation ↑; proliferation ↓</td>
<td>Gene-expression modulation</td>
<td>R, G</td>
<td>Epigenetic reprogramming</td>
<td>Core anticancer mechanism; early-generation, relatively weak HDAC inhibitor.</td>
</tr>

<tr>
<td>2</td>
<td>Cell-cycle arrest</td>
<td>G1 arrest ↑; Cyclin D1 ↓ (reported)</td>
<td>↔</td>
<td>G</td>
<td>Cytostasis</td>
<td>Common downstream effect of HDAC inhibition.</td>
</tr>

<tr>
<td>3</td>
<td>Apoptosis</td>
<td>Caspase activation ↑ (reported; model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Cell death execution</td>
<td>Often secondary to transcriptional changes and stress modulation.</td>
</tr>

<tr>
<td>4</td>
<td>ER stress / Chemical chaperone activity</td>
<td>Context-dependent: ER stress ↑ or ↓</td>
<td>ER stress ↓ (protein misfolding disorders)</td>
<td>R, G</td>
<td>Protein-folding modulation</td>
<td>Acts as chemical chaperone; effect depends on cell type and dose.</td>
</tr>

<tr>
<td>5</td>
<td>NF-κB signaling</td>
<td>NF-κB modulation (reported)</td>
<td>Inflammatory tone modulation</td>
<td>R, G</td>
<td>Transcriptional regulation</td>
<td>Likely secondary to epigenetic changes.</td>
</tr>

<tr>
<td>6</td>
<td>PI3K → AKT / MAPK pathways</td>
<td>Survival pathway modulation (reported; model-dependent)</td>
<td>↔</td>
<td>R, G</td>
<td>Growth signaling modulation</td>
<td>Downstream transcriptional effects rather than primary kinase inhibition.</td>
</tr>

<tr>
<td>7</td>
<td>Mitochondrial stress / ROS</td>
<td>ROS modulation (context-dependent)</td>
<td>↔</td>
<td>P, R, G</td>
<td>Metabolic adaptation</td>
<td>Not a primary ROS-inducing agent; effects vary by tumor model.</td>
</tr>

<tr>
<td>8</td>
<td>Urea-cycle nitrogen scavenging (approved indication)</td>
<td>—</td>
<td>Ammonia elimination ↑ (phenylacetylglutamine formation)</td>
<td>—</td>
<td>Clinical metabolic role</td>
<td>Primary approved medical use.</td>
</tr>
</table>