Ingredients3,5-Dihydroxyphenylacetic acid (abbreviated 3,5-DHPAA) is a naturally occurring low-molecular-weight phenolic acid belonging to the hydroxyphenylacetic acid sub-family of phenolic compounds. It is a monocarboxylic acid with the chemical formula C₈H₈O₄, featuring two hydroxy groups located at the 3 and 5 positions of the benzene ring, making it a member of the resorcinol class of organic compounds. The compound's CAS registry number is 4670-09-1 and its PubChem Compound Identifier (CID) is 597768. 3,5-DHPAA is structurally related to phenylacetic acid, differing primarily in the presence of two hydroxyl substituents, which significantly influence its chemical properties and biological activities.
The compound is also referred to in the literature as:
Its molecular formula is C₈H₈O₄, giving a molecular weight of approximately 168.15 g/mol. The two free phenolic hydroxyl groups at the meta (3-) and meta (5-) positions of the aromatic ring, combined with the acetic acid side chain, define its chemical reactivity and differentiate it structurally from the closely related isomers 3,4-dihydroxyphenylacetic acid (DOPAC, CAS 102-32-9) and 4-hydroxyphenylacetic acid.
It is important to distinguish 3,5-DHPAA from its more extensively studied isomer, 3,4-dihydroxyphenylacetic acid (commonly abbreviated DOPAC), which is a well-known dopamine metabolite in the central nervous system. 3,5-Dihydroxyphenylacetic acid is a naturally occurring organic compound found in various plants, including acacia species and certain ferns, and it is also a metabolite produced in humans from dietary polyphenols. The 3,5-substitution pattern (resorcinol-type) is characteristic of the A-ring degradation fragment of myricetin-type flavonoids, while the 3,4-substitution pattern (catechol-type) is more typical of quercetin- and dopamine-related degradation.
3,5-DHPAA does not typically accumulate in large quantities in intact plant tissues as a free acid. Instead, it arises primarily as a downstream biotransformation product of specific dietary flavonoids, particularly myricetin (3,5,7,3′,4′,5′-hexahydroxyflavone) and related trihydroxy-B-ring flavonoids such as delphinidin, robinetin, and tricetin. The metabolism of a group of polyphenols related in structure to myricetin, including myricetin, myricitrin, 3,4,5-trihydroxyphenylacetic acid, delphinidin, robinetin, tricetin, tricin, malvin, and 5,7-dihydroxy-3′,4′,5′-trimethoxyflavone, has been studied both in vivo after oral administration to the rat and in vitro in cultures of micro-organisms derived from the intestine of the rat.
Plant-level sources of myricetin and other 3,5-dihydroxyphenyl-type precursors include berries, red grapes, red wine, tea, walnuts, and herbs. Myricetin is a flavonoid compound commonly present in fruits, vegetables, tea, berries, and red wine. Foods particularly enriched in the flavonol class—the precursors that give rise to 3,5-DHPAA—include onions, broccoli, tea, apples, and red wine.
In rats administered myricetin orally, the parent compound and seven metabolites were found in plasma, urine, and feces; among these, 3,5-dihydroxyphenylacetic acid (M1) and 3,4,5-trihydroxyphenylacetic acid (M2) were explicitly identified as primary metabolites. This research employed high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS) for characterization.
The primary route of 3,5-DHPAA formation in mammals is colonic microbial ring-fission of the parent flavonoid. Flavonols are extensively hydrolyzed into their metabolite-derivative products by gut microbiota at the A and B rings as a result of the C ring cleavage. The hydroxylation pattern of the A- and B-rings of the parent flavonoid determines the phenolic acid products. The primary gut microbiota metabolites of quercetin are 2-(3,4-dihydroxyphenyl)-acetic acid (from the A-ring) and protocatechuic acid (from the B-ring), while those of myricetin are 2-(3,5-dihydroxyphenyl)-acetic acid (from the A-ring) and gallic acid (from the B-ring).
The degradation proceeds in a stepwise fashion. Flavonols such as kaempferol, quercetin, and myricetin share identical degradation pathways and, after cleavage of the C-ring, are converted to p-hydroxyphenylacetic acid (p-HPAA) and 3,4-dihydroxyphenylacetic acid (DOPAC), with subsequent degradation to m-hydroxyphenylacetic acid (m-HPAA) and 3,4,5-trihydroxyphenylacetic acid with subsequent degradation to 3,5-dihydroxyphenylacetic acid, respectively.
It has been demonstrated that the rat intestinal microflora are able to degrade myricetin-class compounds to the ring-fission products observed in urine after oral administration of the specific flavonoid. Specifically, all flavones and flavonols possessing free 5- and 7-hydroxyl groups in the A ring and a free 4′-hydroxyl group in the B ring give rise to ring-fission products that include 3′,5′-dihydroxyphenylacyl derivatives, including 3,5-DHPAA.
Because 3,5-DHPAA is an end-product of colonic metabolism, it is found in urine and feces following consumption of myricetin-rich foods. The metabolites 3,5-dihydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 3,5-dihydroxyphenylpropionic acid, and 3-hydroxyphenylpropionic acid have been isolated from biological specimens of animals fed myricetin-class polyphenols. More broadly, the compound belongs to the pool of gut-microbiota-derived phenolic metabolites that enter systemic circulation and may contribute to the health effects classically attributed to polyphenol-rich diets. The suppression of oxidative indices in both urine and tissue homogenates has been attributed to the antioxidant efficacy of major metabolites of myricetin and its derivatives, such as 3,5-dihydroxyphenylacetic acid and 3,4,5-trihydroxyphenylacetic acid.
3,5-DHPAA has no documented history of isolated traditional use, and no pharmacopeial monograph or traditional medicine system has recorded its use as a discrete compound. This is expected, because its identity as a discrete molecular entity was established only through modern analytical chemistry. However, the plants that are the richest dietary sources of its precursor flavonoids—particularly myricetin-containing herbs such as bayberry (Myrica rubra), wax myrtle, and a range of Mediterranean dietary staples—have long histories of use in traditional medicine.
Myricetin (3,3′,4′,5,5′,7-hexahydroxyflavone) is a flavonoid found in many natural plants, such as bayberry. Bayberry bark has been used historically in North American and East Asian traditional medicine, and myricetin is also present in abundance in foods central to traditional Mediterranean diets, including red wine, olives, and leafy vegetables. The biological effects now attributed to 3,5-DHPAA and other myricetin metabolites were likely among the unrecognized contributors to the health-promoting properties of these traditional dietary patterns. However, no historical text or traditional medical system identified or intentionally used 3,5-DHPAA as a distinct therapeutic agent.
The scientific identity of 3,5-DHPAA as a distinct myricetin metabolite produced in the mammalian gut was first established in studies of intestinal microbial catabolism of polyphenols, with seminal work published from the 1970s onward characterizing ring-fission products in rat and human urine following polyphenol ingestion.
3,5-Dihydroxyphenylacetic acid is a monocarboxylic acid with the chemical formula C₈H₈O₄, featuring two hydroxy groups at the 3 and 5 positions of the benzene ring, placing it within the resorcinol class of organic compounds. The resorcinol (1,3-benzenediol) substitution pattern differentiates it from the catechol (1,2-benzenediol) pattern seen in DOPAC, and this structural difference has significant implications for its chemistry, including its metal chelation capacity and radical scavenging mechanism.
Myricetin itself is a polyphenol with documented antioxidant, anti-inflammatory, antidiabetic, antitumor, and neuroprotective activities. Myricetin, a naturally occurring flavonol, shows multifarious pharmacological activities, including antidiabetic, antioxidant, anti-inflammatory, antitumor, and liver protection effects. After oral administration, myricetin undergoes extensive first-pass metabolism and colonic biotransformation, and 3,5-DHPAA represents one of the principal identifiable small-molecule end-products of this process. One factor contributing to the complex metabolism of polyphenols is the wide range of metabolites produced; more than 500 polyphenols have been identified, with differing bioactivity and bioavailability due to culinary methods, habitual diet, or consumption of other compounds that may interfere with phase I or II metabolism.
3,5-DHPAA belongs to a chemically coherent class of gut-microbiota-derived phenolic acids that also includes 3-hydroxyphenylacetic acid (3-HPAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and related dihydroxy- and monohydroxy-phenylpropionic acids. Since dietary flavonoid glycosides, including quercetin 4′-glucoside from onion, are poorly absorbed from the gastrointestinal tract, they are converted into smaller phenolic acids, which can then be absorbed into the circulation. This class of metabolites is increasingly studied because, as intact flavonoids have low bioavailability, their metabolites may be the actual bioactive species responsible for health effects observed in epidemiological studies of polyphenol-rich diets. Studies with the bacterial metabolites of polyphenols are needed to explain the actual biological properties in vivo, because they more precisely reflect the physiological conditions than intact polyphenols in vitro.
The primary mechanistic basis proposed for 3,5-DHPAA's biological effects is its capacity to scavenge reactive oxygen species (ROS) and reactive nitrogen species. Research indicates that 3,5-dihydroxyphenylacetic acid exhibits antioxidant properties, scavenging free radicals and thereby protecting cells from oxidative stress. The two phenolic hydroxyl groups on the aromatic ring are the principal structural feature enabling radical scavenging, consistent with structure–activity relationships established across the broader class of dihydroxyphenylacetic acids. The suppression of oxidative indices in both urine and tissue homogenates could be attributed to the antioxidant efficacy of major metabolites of myricetin and its derivatives, such as 3,5-dihydroxyphenylacetic acid, 3,4,5-trihydroxyphenylacetic acid, gallic acid, and quercetin.
Among structurally related dihydroxyphenylacetic acids, the catechol isomer (3,4-DHPAA/DOPAC) has been more extensively characterized. 3,4-Dihydroxyphenylacetic acid (3,4-DHPA) is a naturally occurring phenolic acid exhibiting strong free radical scavenging activity; it can reduce lipid peroxidation and may be potentially used as a natural antioxidant to replace butylated hydroxytoluene (BHT) and butylated hydroxyanisol (BHA) for stabilization of edible oils. By structural analogy, the 3,5-resorcinol isomer is expected to share many of these mechanisms, although direct comparative data are limited.
Studies have shown the potential of 3,5-dihydroxyphenylacetic acid to reduce inflammation markers in various biological models. For structurally related dihydroxyphenylacetic acid metabolites, the anti-inflammatory mechanism has been more thoroughly characterized: 3,4-DHPA has been shown to inhibit the secretion of pro-inflammatory cytokines in lipopolysaccharide-stimulated peripheral blood mononuclear cells and the expression of P-selectin. Similar NF-κB-mediated and cytokine-suppression pathways are hypothesized for 3,5-DHPAA based on structural similarity, but specific mechanistic data for the 3,5-isomer are sparse in the peer-reviewed literature.
Among the class of dihydroxyphenylacetic acids derived from flavonoid catabolism, induction of phase II cytoprotective enzymes has been documented. Studies examining the catabolites of quercetin glycosides found that both DOPAC (3,4-DHPAA) and protocatechuic acid, having a catechol moiety, exhibited both DPPH radical scavenging and superoxide dismutase-like activities. For DOPAC specifically, DOPAC significantly inhibited hydrogen peroxide-induced cytotoxicity in hepatocytes with enhancement of total glutathione S-transferase activity. Whether 3,5-DHPAA shares these enzymatic induction properties has not been definitively established in published peer-reviewed studies as of the available evidence.
The mechanism of action of 3,5-DHPA remains largely unknown. Due to its structural similarity to some biologically active compounds, such as dopamine and certain phenolic antioxidants, researchers are exploring its potential roles in various biological systems. However, more research is required to understand its specific interactions and mechanisms. This is a significant caveat: as of current published literature, most mechanistic understanding of 3,5-DHPAA is extrapolated from studies of its structural analogs, particularly 3,4-DHPAA.
Evidence grade: Preliminary; largely based on the parent compound (myricetin) and structural analogs; direct 3,5-DHPAA data are limited.
The most direct evidence for 3,5-DHPAA's antioxidant contributions comes from metabolite studies in animal models. In rat studies examining myricetin metabolism, the compound was isolated as a urinary metabolite alongside reductions in oxidative stress markers, with investigators attributing antioxidant effects to the pool of phenolic metabolites that includes 3,5-DHPAA. The suppression of oxidative indices in both urine and tissue homogenates has been attributed to the antioxidant efficacy of major metabolites of myricetin and its derivatives, including 3,5-dihydroxyphenylacetic acid. However, these studies do not isolate the specific contribution of 3,5-DHPAA from that of co-occurring metabolites.
For the structurally related 3,4-isomer (DOPAC), direct antioxidant studies have been conducted in vitro. In one study examining catabolites of quercetin 4′-glucoside, the purpose was to compare the effects of major phenolic acid catabolites of quercetin 4′-glucoside, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-hydroxyphenylacetic acid, 3,4-dihydroxybenzoic acid (protocatechuic acid), and hippuric acid, on antioxidant activity and phase II cytoprotective enzyme induction in vitro. These in vitro findings from analogs suggest a plausible mechanism, but do not constitute direct evidence for 3,5-DHPAA.
Evidence grade: Mechanistic and observational; no dedicated clinical trials on 3,5-DHPAA.
3,5-DHPAA is produced in and released from the colon following microbial breakdown of myricetin and related flavonoids. The hydroxylation pattern of A- and B-rings affects the type of phenolic compounds produced, which will be finally absorbed at the colon level. The compound thus arises from and directly interacts with the colonic environment, and its production is indicative of the activity of specific ring-cleaving gut bacteria. Its formation is functionally linked to the colonic microbiota composition and may serve as a biomarker of myricetin intake and colonic metabolic activity.
The importance of these metabolite-producing bacteria has been emphasized in polyphenol bioavailability research. The interest in fermented products formed by the colonic microbiota in the large intestine, including the metabolites of polyphenols as well as short-chain fatty acids, and their role in bowel diseases has started to rapidly grow. No dedicated clinical trials have examined 3,5-DHPAA specifically in the context of gastrointestinal disease outcomes.
Evidence grade: Preclinical/indirect; no clinical trials on 3,5-DHPAA.
Epidemiological associations between polyphenol-rich diets and reduced cardiovascular risk are well documented, and gut-derived phenolic acids are considered plausible bioactive effectors. For the structurally related 3-hydroxyphenylacetic acid (3-HPAA), a gut microbiota metabolite of flavonols, direct preclinical cardiovascular evidence has been published: 3-hydroxyphenylacetic acid (3-HPAA), formed by the gut microbiota, was previously reported to exert vasorelaxant effects ex vivo. 3-HPAA gave rise to a dose-dependent decrease in arterial blood pressure when administered intravenously both as a bolus and infusion to spontaneously hypertensive rats, with no significant changes in heart rate observed. Whether 3,5-DHPAA shares these vascular effects is currently unknown.
For 3,4-DHPAA (DOPAC), cardiovascular relevance has been explored indirectly: it is a predominant biologically-active catabolite of dietary quercetin glycosides and exhibits protective effects against apoptosis, mitochondrial dysfunction, and oxidative stress. Given the structural similarity between the two isomers, analogous cardiovascular-protective properties for 3,5-DHPAA are plausible, but not directly demonstrated in published studies.
Evidence grade: Indirect/preclinical; no dedicated 3,5-DHPAA neuroprotection trials.
The neuroprotective properties ascribed to myricetin and its metabolites provide a relevant backdrop for considering 3,5-DHPAA's potential neurological effects. Myricetin and its degradation products, including 3,5-DHPAA, are produced in the gut following consumption of myricetin-rich foods and subsequently enter systemic circulation. One of the beneficial biological effects of myricetin is neuroprotective activity, showing preclinical activities on Alzheimer's, Parkinson's, and Huntington's diseases, and even in amyotrophic lateral sclerosis.
Regarding the broader class of phenolic acids, 3,5-DHPAA may offer protective benefits against neurodegenerative diseases by modulating neurotransmitter levels and reducing neuronal damage. However, this claim is based on structural inference and has not been directly substantiated in published peer-reviewed clinical or animal-model studies specifically using 3,5-DHPAA as the test compound. Caution is warranted in attributing the neuroprotective effects of myricetin to 3,5-DHPAA specifically, as multiple metabolites and the parent compound itself contribute to observed effects.
Evidence grade: Indirect; based on class-level evidence.
Myricetin, the principal dietary precursor of 3,5-DHPAA, shows multifarious pharmacological activities including antidiabetic effects. Several gut-derived phenolic acid metabolites structurally related to 3,5-DHPAA have been explored for effects on glucose metabolism. For the 3,4-isomer DOPAC, a study in type 2 diabetic mice found that DHAA alleviated hyperglycemia and decreased insulin resistance; the study aimed to investigate whether 3,4-dihydroxyphenylacetic acid can improve gut barrier function by inhibiting the MAPK-MLCK signaling pathway in type 2 diabetes mice. Whether 3,5-DHPAA shares these metabolic effects has not been specifically studied.
Evidence grade: Indirect; no published clinical trials; class-level in vitro data only.
Anti-inflammatory activity is a property shared by multiple dihydroxyphenylacetic acid isomers. For DOPAC (3,4-DHPAA), inhibition of pro-inflammatory cytokine secretion in human peripheral blood mononuclear cells (PBMCs) has been documented. The effect of 3,4-dihydroxyphenylacetic acid on modulation of the production of the main pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) had been confirmed; the production of these cytokines by lipopolysaccharide-stimulated peripheral blood mononuclear cells pre-treated with the phenolic metabolite was studied in healthy volunteers, with the dihydroxylated compound significantly inhibiting the secretion of these pro-inflammatory cytokines. For 3,5-DHPAA specifically, there are no published studies of comparable design and quality. Structural analogy to DOPAC is frequently cited but does not substitute for direct experimental evidence.
3,5-DHPAA is commercially available as a research-grade analytical standard and chemical reference material, listed in chemical catalogs at CAS 4670-09-1. It is not known to be formulated as a stand-alone dietary supplement product. As a dietary supplement ingredient, no dedicated product formulation has been identified in regulatory databases (such as the US FDA Dietary Supplement Ingredient Advisory List or EMA/EFSA databases) that lists 3,5-DHPAA as a primary active ingredient.
In research contexts, it is studied as:
Preparations of myricetin-rich plants—such as wax myrtle bark, bayberry, and blueberry extracts—that are commercially available as dietary supplements would be expected to generate 3,5-DHPAA as a colonic metabolite upon consumption, but this metabolite is not listed or characterized in such product labeling.
No clinical trials have administered isolated 3,5-DHPAA to human subjects. There are therefore no human dosage data for this specific compound. Dosage information available relates to the precursor compound myricetin or to the structural analog DOPAC in animal models.
In the type 2 diabetes mouse model study using the structurally analogous 3,4-DHPAA, T2D mice were intragastrically administered with DHAA at 75 and 150 mg/kg body weight per day for 4 weeks. These doses in rodent models are not directly translatable to human supplementation guidance without dedicated pharmacokinetic and dose-finding studies.
In a crossover pharmacokinetic study examining hydroxytyrosol (a related olive-derived phenol whose metabolism partly generates 3,4-DHPAA), researchers investigated the impact of hydroxytyrosol bioavailability by comparing two olive-derived supplements containing different doses of HT (30.58 and 61.48 mg of HT/dosage) in 12 healthy volunteers, who provided plasma and urine samples. Again, this relates to the 3,4-isomer and its precursor, not 3,5-DHPAA directly.
Formal toxicological characterization of 3,5-DHPAA as an isolated compound is absent from the peer-reviewed literature available for this review. No regulatory body (FDA, EFSA, EMA, or WHO) has published a safety assessment specifically addressing 3,5-DHPAA as a dietary supplement ingredient.
The compound is a normal, low-level constituent of human urine following consumption of myricetin-rich foods, implying a degree of physiological tolerability at endogenously generated quantities. The rat intestinal microflora are able to degrade myricetin-class compounds to the ring-fission products observed in urine after oral administration, indicating that the compound is absorbed, circulates, and is renally excreted without acute toxicity in animal models at dietary-relevant concentrations.
3,5-DHPAA is structurally related to a broad class of dietary phenolic acids that are generally regarded as safe (GRAS-status phenolic acids such as gallic acid, protocatechuic acid, and related compounds are consumed in gram quantities in plant-rich diets). Its resorcinol backbone is present in natural dietary compounds consumed regularly without known acute adverse effects at physiological concentrations. However, high-dose resorcinol compounds can have thyroid-suppressing effects in some contexts, and this has not been specifically investigated for 3,5-DHPAA at supplemental doses.
No documented pharmacokinetic or pharmacodynamic drug interactions have been identified in the peer-reviewed literature for 3,5-DHPAA specifically. As with other polyphenol metabolites, theoretical interactions with drug metabolism enzymes (CYP450 family) are possible given the structural characteristics of phenolic acids, but no direct interaction studies have been published for this compound. The production of 3,5-DHPAA from dietary myricetin is dependent on the composition of the gut microbiome, meaning that antibiotic use or microbiome-altering interventions could reduce its formation from precursor flavonoids, thereby potentially modifying any of its biological effects observed in microbiome-intact subjects.
The scientific characterization of 3,5-DHPAA as a pharmacologically active compound remains at an early stage. The following limitations apply to the current evidence base:
Despite the hypothesized importance of polyphenol metabolites, findings from human studies have been inconsistent because it is challenging to rigorously study the direct health effects of polyphenols due to their complex metabolism. This challenge applies with particular force to 3,5-DHPAA, a downstream microbial catabolite whose production depends on multiple variables including host genetics, microbiome composition, and dietary context.
Health conditions that 3,5-dihydroxyphenyl acetate may help support.
Body systems that 3,5-dihydroxyphenyl acetate may help support.
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