4-Hydroxyphenylacetic acid (6, 12, or 25 mg/kg) stimulates phase II and antioxidant enzyme activity as well as Nrf2 translocation to the nucleus. When compared to the control group, the pre-treated groups receiving 12 and 25 mg/kg 4-hydroxyphenylacetic acid had protein levels of nuclear Nrf2 that were 170% and 230% higher, respectively. The phase II enzyme target genes were significantly and selectively up-regulated by the 4-Hydroxyphenylacetic acid pretreatment at a final dose of 25 mg/kg. This up-regulation was greater than that of the control group by 270%, 400%, and 500%, or UGT1A1, UGT1A9, and SULT2A1, respectively. 4-Hydroxyphenylacetic acid likewise inhibits CYP2E1 expression[1].

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Pretreatment with 4-HPA (6, 12, or 25 mg/kg/day for 3 days) dose-dependently prevented the increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities induced by a single intraperitoneal dose of acetaminophen (APAP, 300 mg/kg) in mice.[1]
4-HPA pretreatment dose-dependently alleviated APAP-induced histopathological liver injuries, including massive necrosis, centrilobular ballooning degeneration, sinusoidal congestion, and lymphocyte infiltration. Pretreatment with 25 mg/kg 4-HPA resulted in liver tissue appearance almost normal, with only a few swollen hepatocytes.[1]
4-HPA pretreatment significantly inhibited APAP-induced oxidative stress in the liver. It prevented the depletion of glutathione (GSH) and the decrease in the activities of antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). It also reduced the elevated level of malondialdehyde (MDA), a lipid peroxidation product.[1]
4-HPA pretreatment dose-dependently decreased the formation of 3-nitrotyrosine (3-NT) protein adducts induced by APAP overdose, indicating inhibition of peroxynitrite-mediated nitrative stress.[1]
4-HPA pretreatment significantly suppressed the increased expression of CYP2E1 protein and mRNA induced by APAP alone.[1]
4-HPA pretreatment enhanced the activities and mRNA expression of hepatic phase II enzymes. It increased the protein levels of glutathione S-transferase (GST), sulfotransferases (SULTs), and UDP-glucuronosyltransferases (UGTs) in a dose-dependent manner. Notably, the highest dose (25 mg/kg) markedly up-regulated the mRNA levels of UGT1A9 and SULT2A1.[1]
4-HPA pretreatment induced the nuclear translocation of Nrf2. It increased the protein levels of nuclear Nrf2 and up-regulated the mRNA expression of Nrf2 and its downstream target gene, glutamate-cysteine ligase catalytic subunit (GCLC), in a dose-dependent manner.[1]
The protective effects of 4-HPA (25 mg/kg) against APAP-induced liver injury were comparable to, and in some aspects (e.g., restoring CAT and SOD levels) potentially better than, those of the positive control N-acetylcysteine (NAC, 100 mg/kg).[1]

Male Kunming mice (6 weeks old, 20-25 g) were randomly assigned to six groups: Control (saline), APAP-only (300 mg/kg), NAC+APAP (100 mg/kg NAC + 300 mg/kg APAP), and three 4-HPA pretreatment groups (4HPA6+APAP, 4HPA12+APAP, 4HPA25+APAP).
4-HPA (purity not specified) was dissolved in 0.9% saline solution immediately before use.
4-HPA was administered by intragastric gavage (oral) at doses of 6, 12, or 25 mg/kg body weight per day for three consecutive days.
One hour after the last administration of 4-HPA, NAC, or saline, a single dose of APAP (300 mg/kg) was administered intraperitoneally to induce liver injury in all groups except the Control.
Mice were euthanized 24 hours after APAP administration for sample collection.[1]

Metabolism / Metabolites
Known metabolites of 4-hydroxyphenylacetic acid include 2-phenylacetic acid. 4-Hydroxyphenylacetic acid is a known metabolite of 3,4-dihydroxyphenylacetic acid.

Preliminary experiments found that pretreatment with 4-HPA at doses of 50 mg/kg and 100 mg/kg for 3 days enhanced acetaminophen (APAP)-induced hepatotoxicity, suggesting that higher doses of 4-HPA may have potential toxicity or adverse reactions in this model. [1]

[1]. 4-Hydroxyphenylacetic Acid Prevents Acute APAP-Induced Liver Injury by Increasing Phase IIand Antioxidant Enzymes in Mice. Front Pharmacol. 2018 Jun 19;9:653.

4-Hydroxyphenylacetic acid (4-HPA) is a monocarboxylic acid, a derivative of acetic acid in which one methyl hydrogen atom is replaced by a 4-hydroxyphenyl group. It is found in plants, fungi, humans, and mice as a metabolite. It belongs to the monocarboxylic acid class and is a member of the phenolic class, functionally related to acetic acid. It is the conjugate acid of 4-hydroxyphenylacetic acid. 4-HPA has been reported in Epichloe typhina, Oenothera glazioviana, and other organisms with relevant data. 4-HPA is a metabolite found in or produced by Saccharomyces cerevisiae. 4-HPA is a major microbial-derived metabolite of dietary polyphenols such as proanthocyanidins and kaempferol. 4-HPA possesses a variety of reported biological activities, including anti-anxiety and antiplatelet aggregation effects.
In this acetaminophen (APAP)-induced acute liver injury model, 4-HPA is thought to exert a hepatoprotective effect through two main pathways: First, by downregulating the expression of CYP2E1, thereby reducing the production of ... First, 4-HPA can inhibit the production of the toxic metabolite NAPQI; second, it can activate the Nrf2 signaling pathway, leading to the upregulation of antioxidant enzymes (such as SOD, CAT, GPx, GSH) and phase II detoxification enzymes (such as GST, SULTs, UGTs), thereby jointly enhancing the detoxification effect of APAP and combating oxidative stress. [1]
The molecular docking studies cited in the article show that the interaction between 4-HPA and CYP2E1 may be stronger than that of its isomer 3,4-HPA, and its docking score for Nrf2 and CYP2E1 is comparable to that of 3,4-HPA and higher than that of the standard drug N-acetylCysteamine. [1]
This study primarily investigated the preventive effect of 4-HPA; its potential therapeutic (cure) effect after acetaminophen (APAP)-induced injury has not been evaluated. [1]
The concentration of endogenous circulating 4-HPA in rat plasma was approximately 410 ng/mL or 2.7 µM. [1]

C8H8O3

152.1473

152.047

156-38-7

127

Off-white to light yellow solid powder

1.3±0.1 g/cm3

346.6±17.0 °C at 760 mmHg

148-151 °C(lit.)

177.6±17.4 °C

0.0±0.8 mmHg at 25°C

1.596

0.77

2

3

2

11

136

0

XQXPVVBIMDBYFF-UHFFFAOYSA-N

InChI=1S/C8H8O3/c9-7-3-1-6(2-4-7)5-8(10)11/h1-4,9H,5H2,(H,10,11)

2-(4-hydroxyphenyl)acetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~657.25 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.43 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (16.43 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (16.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)