3,4-Dihydroxyhydrocinnamic Acid

3,4-Dihydroxyhydrocinnamic acid (DHCA) is a phenolic acid metabolite derived from dietary polyphenols and produced by gut bacteria such as Bifidobacterium, Escherichia, Lactobacillus, and Clostridium. 

Following ingestion of polyphenol-rich foods, DHCA is formed and eventually excreted in urine after undergoing phase II metabolism in the liver.  

Its presence can serve as a biomarker for dietary intake of plant-based or polyphenol-rich foods, and adherence to diets like the Mediterranean diet. 

Structurally, DHCA comprises a benzene ring with hydroxyl groups at the 3 and 4 positions and a propionic acid side chain, resembling the structure of dopamine.  This similarity suggests potential interactions or overlapping metabolic pathways between DHCA and dopamine, which could have implications for neurobiological processes and health.

DHCA exhibits potent antioxidant, anti-inflammatory, antimicrobial, and other health-beneficial properties due to its unique catechol structure. 

It demonstrates higher antioxidant reactivity than its precursor, caffeic acid, by reducing ferric iron and scavenging free radicals.  Moreover, DHCA has shown to inhibit the production of inflammatory mediators, offering protective effects against oxidative stress and inflammation. 

These diverse biological activities contribute to DHCA's potential in promoting human health and mitigating oxidative stress, inflammation, and related chronic diseases.

What is 3,4-Dihydroxyhydrocinnamic acid (DHCA)?  Chemical Properties and Synthesis of 3,4-Dihydroxyhydrocinnamic Acid

DHCA is a microbial metabolite of dietary polyphenols, and an organic acid.  It is produced by gut bacteria in the presence of polyphenol-rich foods that is excreted in the urine after undergoing phase II metabolism in the liver.  [9., 16.] 

It is created by bacteria including Bifidobacterium, Escherichia, Lactobacillus, and Clostridium.  [6.] 

It can be used to assess recent dietary intake of plant-based or polyphenol-rich foods, and/or adherence to dietary plans such as the Mediterranean diet.  [11.] 

Chemical Structure of 3,4-Dihydroxyhydrocinnamic Acid (DHCA)  [9.] 

The chemical structure of 3,4-dihydroxyhydrocinnamic acid (DHCA) consists of a benzene ring substituted with two hydroxyl groups at the 3 and 4 positions, and a propionic acid side chain. 

This structure, also known as a catechol structure, is structurally similar to dopamine, which may play a role in DHCA’s understood relationship with dopamine.  

Properties and Health Benefits of 3,4-Dihydroxyhydrocinnamic Acid (DHCA)  [9., 16.] 

3,4-Dihydroxyhydrocinnamic acid (DHCA) is a phenolic acid metabolite formed from the hydrogenation of caffeic acid and other caffeoylquinic acids in the human body after ingesting polyphenol-rich foods like coffee and artichoke.

It is also found in many medicinal herbs including chamomile, Isatis tinctoria, Gynura bicolor, Nepeta teydea, Asian spicebush, spikemoss and others.  Additionally, DHCA can be created from the polyphenols found in olives, olive oil, red wine, natural ciders, beets, and some grains.  [11., 16.] 

It is bioavailable and can reach biologically relevant concentrations in plasma.  

DHCA exhibits potent antioxidant activity by reducing ferric iron, scavenging free radicals, and protecting cells from oxidative stress due to its unique catechol structure.  It has demonstrated higher antioxidant reactivity than its precursor caffeic acid in certain environments.

Additionally, DHCA and its derivatives have shown anti-inflammatory effects by inhibiting production of inflammatory mediators like prostaglandin E2 and interleukin-6 in cellular studies.  [16.] 

Beyond its antioxidant and anti-inflammatory properties, DHCA has displayed antimicrobial, antibiofilm, lipid-lowering, anti-diabetic, and anti-amyloid aggregation effects in various studies.  [16.] 

These diverse biological activities of DHCA, stemming from its unique structure as a metabolite of dietary polyphenols, contribute to its potential for promoting human health by mitigating oxidative stress, inflammation, and associated chronic diseases.

Specific Health Benefits of 3,4-Dihydroxyhydrocinnamic Acid (DHCA)  [16.] 

Antioxidant Activity

DHCA and its derivatives demonstrate strong antioxidant properties, capable of scavenging free radicals and protecting cells from oxidative damage. It has shown superior activity in various assays compared to other phenolic acids.

It is also known to reduce the proxidant ferric form of iron in FRAP assays, which may contribute to its antioxidant activity.  [6.]

Anti-Inflammatory Activity

DHCA reduces inflammation by inhibiting the production of pro-inflammatory cytokines and reducing oxidative stress markers. It has been effective in mitigating colitis in animal models and reducing inflammation in human cell studies.

Cytoprotective Activity

DHCA protects cells from UVB-induced damage and chemical toxicity. It enhances cell survival and reduces DNA damage, making it a potential candidate for topical treatments against UV damage and other oxidative stress-related conditions.

Anticancer Activity

DHCA and its esters exhibit cytotoxic effects on various cancer cell lines, with some derivatives showing potent anticancer activities. It is also used in novel drug delivery systems for cancer treatment.

Enzyme Inhibitory Activity

DHCA and its derivatives inhibit several enzymes including tyrosine kinase, histone deacetylase, and insulin-degrading enzyme, showing potential for therapeutic applications in conditions like cancer, diabetes, and inflammation.

Antimicrobial Activity

DHCA demonstrates antimicrobial properties against a range of bacteria including antibiotic-resistant strains, and reduces biofilm formation. Its derivatives have also shown significant antibacterial activity.

Antiviral Activity

Polymers synthesized from DHCA inhibit herpes simplex virus type 1 (HSV-1) and show activity against other viruses, including influenza A and cytomegalovirus.

Repellent Activity

DHCA has been identified as a water-soluble repellent, affecting nematode behavior and potentially useful in pest control.

3,4-Dihydroxyhydrocinnamic Acid (DHCA)’s Relationship With Dopamine, and Association with Neurodegenerative and Inflammatory Disorders  [5.]

Dihydrocaffeic acid (DHCA) is a phenolic acid.  Its structure includes a catechol moiety and a three-carbon side chain with a carboxyl group, which resembles the structure of dopamine, a significant neuromodulatory molecule.

After ingesting foods rich in chlorogenic and caffeic acids, DHCA is detectable in plasma, urine, or feces.  The intestinal microbiota plays a crucial role in metabolizing these compounds. 

Studies have shown that DHCA appears in plasma primarily as dihydrocaffeic acid 4'-O-sulfate after coffee consumption.  This formation results from the reduction and methylation processes that chlorogenic and caffeic acids undergo due to the action of intestinal bacteria. 

The formation of DHCA is a complex process involving the shikimate pathway, which produces aromatic amino acids like phenylalanine and tyrosine, precursors for phenolic compounds.  Tyrosine 3-monooxygenase converts tyrosine to 3,4-dihydroxy-L-phenylalanine (L-Dopa), which can be further metabolized to DHCA. 

Another route to DHCA is through the reduction of the double bond in caffeic acid by an NADPH-dependent enzyme, indicating multiple biosynthetic pathways for DHCA in nature.

The structural resemblance between DHCA and dopamine suggests potential interactions or overlapping metabolic pathways.  The metabolism of tyrosine to L-Dopa, a precursor to dopamine, shares intermediates with DHCA biosynthesis.  

This indicates a biochemical link between the pathways of dopamine and DHCA and suggests possible interactions with dopaminergic systems, warranting further research into its neurobiological effects.

Elevated Dopamine, Inflammation, and Neurodegeneration  [5., 10.] 

Dopamine (DA) metabolism is intrinsically linked to oxidative stress, as its degradation generates reactive oxygen species (ROS), and DA oxidation can produce neurotoxins. 

Conversely, some DA derivatives have antioxidative properties, making DA metabolism crucial for neuronal redox-homeostasis and viability.  DHCA is an antioxidant dopamine-like metabolite of dietary polyphenols, but its presence may affect dopamine levels as discussed above.  

Therefore, elevated DHCA levels may indicate an increase in dopamine metabolism which promotes inflammation and can produce neurotoxins; testing for dopamine metabolites may be a consideration when assessing an individual’s DHCA levels.  

What Are Organic Acids?  [3., 4.]

Organic acids are organic compounds with acidic properties.  They include a variety of functional groups like carboxyl, phenol, enol, and thiol, with carboxylic acids having the strongest acidity.

Organic acids are considered weak acids, with those containing phenol, enol, alcohol, or thiol groups being even weaker.  

Their structures vary in terms of carbon chain types—aromatic, aliphatic, alicyclic, heterocyclic—saturation, substitutions, and the number of functional groups. 

These acids play critical roles in metabolic and catabolic pathways, notably in the tricarboxylic acid cycle inside mitochondria, which is central to energy production in eukaryotes.  They are also pivotal in determining the sensory properties of fruits and vegetables.

Organic Acid Disorders  [2., 14.]

Organic acid disorders are inherited metabolic conditions that affect the enzymes or transport proteins essential for the breakdown of amino acids, lipids, or carbohydrates. They are marked by the excessive excretion of non-amino organic acids in urine, primarily due to defects in specific enzymes involved in amino acid breakdown that cause buildup of organic acids in tissues.

Conditions can manifest as inborn metabolic disorders of organic acids and amino acids, urea cycle anomalies, and mitochondrial respiratory chain deficiencies.

These disorders are typically passed down through autosomal recessive inheritance.  They often present in newborns with symptoms like vomiting and lethargy, progressing to more severe neurological symptoms. 

Early diagnosis and intervention are critical and can improve outcomes. Diagnostic methods include urine organic acid analysis via gas chromatography-mass spectrometry (GC/MS). 

Current treatments focus on managing symptoms and preventing complications, although definitive therapies are still under research.  Treatment focuses may include dietary management, detoxifying harmful metabolites, and in severe cases, organ transplantation. 

Continuous monitoring and management are essential for managing symptoms and preventing complications.

Organic Acids and the Microbiome  [7.]

Increasingly, research highlights new relationships between the microbiome and human health.  Many organisms that comprise the microbiome produce organic acids that can then be tested for additional diagnostic capability.  

Certain organic acids in urine like hippuric acid, benzoic acid, and indoleacetic acid are metabolites produced by gut bacteria from the breakdown of amino acids, dietary polyphenols, and other substances. 

These acids provide insights into gut health and metabolic functions.  For example, elevated levels of certain acids may indicate gut dysbiosis or specific metabolic imbalances, such as phenylketonuria. 

Organic Acid Testing in Functional Medicine

Organic Acid Testing in Functional Medicine

In functional medicine, organic acid testing is utilized to evaluate a patient's metabolic function through a simple urine test. This testing can identify metabolic imbalances that may affect a patient’s mood, energy, and overall health. 

Testing provides insights into nutrient deficiencies, dietary habits, toxic exposures, and gut microbiome activity. 

The results assist practitioners in customizing treatment plans to address specific metabolic dysfunctions and improve health outcomes. 

Additionally, it helps in assessing the impact of microbial metabolism and the efficiency of the Krebs Cycle, aiding in personalized healthcare.

Laboratory Testing for 3,4-Dihydroxyhydrocinnamic acid (DHCA)

Test Information, Sampling Methods and Preparation

Laboratory testing for organic acids including 3,4-Dihydroxyhydrocinnamic acid (DHCA) is typically done in urine, although it can also be tested in blood.  Testing may be ordered to diagnose an inborn metabolic disorder, or to assess metabolic function and gastrointestinal health in a functional medicine setting.  

Urine samples may be collected in a clinical setting; they can also be collected at home.  Some labs recommend or require a first morning void sample, to provide a concentrated sample.  

Interpreting 3,4-Dihydroxyhydrocinnamic acid (DHCA) Results

Optimal Range for 3,4-Dihydroxyhydrocinnamic acid (DHCA) Testing

Generally, falling within reference ranges for organic acids is recommended, although for many of these organic acids, a level towards the lower end of the reference range is considered optimal.  

In the case of DHCA, an optimal level is considered anything below the upper threshold, although some DHCA may be beneficial as it demonstrates many health benefits.  Interpretation of DHCA levels should include an assessment of the individual’s overall organic acids profile and may include other markers such as dopamine metabolites and markers of inflammation.  

It is essential to consult with the laboratory company used for their recommended reference range for 3,4-Dihydroxyhydrocinnamic acid (DHCA).  

One company reports the following reference range for 3,4-Dihydroxyhydrocinnamic Acid (DHCA):  < 1490.3 nmol/mg Creatinine  [13.]

Clinical Significance of Elevated Levels of 3,4-Dihydroxyhydrocinnamic Acid (DHCA)

Elevated 3,4-Dihydroxyhydrocinnamic Acid (DHCA) levels above the upper threshold may indicate an increase in dopamine metabolism, which is associated with increased reactive oxygen species, inflammation, and has been implicated in neurodegenerative diseases.

The presence of DHCA below the upper threshold generally indicates adherence to a plant-based and/or Mediterranean diet, as well as recent coffee intake, and this alone should be considered a beneficial finding.  

Clinical Significance of Low Levels of 3,4-Dihydroxyhydrocinnamic Acid (DHCA)

Low levels of 3,4-Dihydroxyhydrocinnamic Acid (DHCA) are generally not considered clinically relevant.  However, if this marker is used to assess adherence to a dietary plan such as the Mediterranean diet, the absence of DHCA indicates a lack of recent intake of Mediterranean diet staples such as olives and olive oil.  

3,4-Dihydroxyhydrocinnamic Acid (DHCA) Related Biomarkers and Comparative Analysis

3,4-Dihydroxyhydrocinnamic Acid (DHCA) is typically tested along with other organic acids to gain deeper insights into metabolic pathways and physiological processes.

As discussed above, 3,4-Dihydroxyhydrocinnamic Acid (DHCA) may also be tested in conjunction with markers of dopamine metabolism such as homovanillic acid (HVA), as well as markers of neurological inflammation such as quinolinic acid, kynurenine, and their relationship.  

Quinolinic Acid (QA) Levels  [1., 12.] 

QA is a metabolite in the kynurenine pathway and is considered a biomarker of neuroinflammation and neurotoxicity. Elevated QA levels are associated with hyperalgesia, chronic pain in neurodegenerative and psychiatric disorders, and excitotoxicity via NMDA receptor agonism.

Kynurenic Acid (KA) Levels [1., 12.]

KA is another kynurenine pathway metabolite that exhibits neuroprotective and anti-inflammatory properties.  Diminished KA levels may indicate poor inflammatory regulation, while elevated levels suggest an upregulated response to inflammation and pain.

Kynurenic Acid/Quinolinic Acid Ratio (KA/QA ratio)  [1., 12.]

A lower KA/QA ratio indicates a lack of neuroprotection relative to neurotoxicity.

Kynurenine/Tryptophan Ratio (KYN/Trp ratio)  [1., 12.] 

Higher KYN/Trp ratios suggest increased inflammation and shunting of tryptophan towards the kynurenine pathway instead of serotonin production.  

Homovanillic Acid (HVA)  [8., 15.] 

HVA is a major metabolite of dopamine produced through the catabolism of dopamine by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) enzymes.  Measuring HVA levels in biological fluids like plasma, cerebrospinal fluid (CSF), or urine can provide an indirect assessment of central dopaminergic activity and dopamine turnover in the brain.

In neurodegenerative conditions like Parkinson's disease (PD) and schizophrenia, abnormalities in dopamine metabolism and signaling play a key role in pathogenesis.  Altered HVA levels can indicate disruptions in dopamine homeostasis associated with these disorders.

Order Organic Acids Testing

Click here to compare testing options and order organic acid testing.