Uric Acid

A Metabolic Perturber Worth Targeting

BY DR. BAYNE FRENCH

Prefatory Comments by Steve Born: Elevated uric acid (UA) levels are something you want to avoid at all costs. Not only do high UA levels lead to two of the most painful issues you never want to experience—gout and kidney stones—they are also responsible for an increased risk of many metabolic issues, such as high blood pressure, elevated blood sugar levels and greater potential for insulin resistance, increased body weight, and inflammation. Thankfully, along with some dietary tweaks on your part, there are nutrients that, working in combination, will reduce UA levels. These nutrients, in specific amounts, are found in the new Uric X, formulated by Hammer Nutrition’s Chief Medical Advisor, Dr. Bayne French. Read on for more on UA, the unwanted health issues that elevated UA levels cause, the dietary steps we need to take to avoid elevated UA levels, and the powerful new URIC X formula…

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Tell me something I Care About:

• Historically considered a benign metabolic byproduct only important in the setting of gout, uric acid (UA) is now known to disturb healthy metabolism in many ways.
  
  
• Uric acid increases blood pressure, blood sugar, body weight, and triggers inflammation.
  
  
• There are 6 main drivers of UA formation in humans: sugar, alcohol, purines, insulin resistance, genetics, and vigorous exercise.
  
  
• Medical providers typically don’t screen for UA elevation. Nor do the vast majority of them understand the metabolic consequences of elevated UA. Nor do they even understand basic human metabolism to begin with.
  
  
• Despite their metabolic understanding shortcomings, your medical provider can order labs. Request that they order a UA test.
  
  
• Dietary improvements commonly result in lower UA levels, but not always. Prescription medications are very effective but not desirable for many individuals, and may have side effects. The medication allopurinol targets the enzyme that makes UA, xanthine oxidase (XO).
  
  
• There are several supplemental compounds, when used in proper combination and dosages, that are capable of significant UA level reductions.
  
  
• Uric X has been formulated to synergistically reduce UA levels by numerous mechanisms: inhibition of XO, enhanced kidney excretion of uric acid, anti-inflammation, anti-oxidation.

Human History with Uric Acid:

UA is a compound consisting of carbon, nitrogen, oxygen and hydrogen. It is the end-product of purine metabolism, formed in a multi-step manner.

Purines are nitrogen containing organic compounds found in high concentration in meat and meat products. Lentils, mushrooms, peas, spinach, asparagus, oatmeal, cauliflower and other non-animal product also purine dense. So is beer.

According to George et al. (StatPearls. 2021), 21% of the US population has elevated UA levels. Is that because they’re metabolically unwell? Probably, but there are genetic influences at work as well, that conferred us sapiens with survivalistic advantages by:

• Driving fat formation (lipogenesis)
• Raising blood pressure.
• Raising blood sugar.
• Promoting weight gain (caloric storage).
• Increasing inflammation.
• Reducing urination thus increasing body fluid and blood volume.

You might be wondering, how in any way is this list favorable for our survival? Because old age was 28! Having more body fat in the event of starvation; more blood volume in the event of hemorrhage; and more inflammation to kill germs and lay down scar tissue was favorable for a respective early hominoid making it to a child bearing age.

Elevated UA provided a survivalistic advantage. So much so that we (and other mammals) found a way to completely silence the enzyme that breaks down UA, uricase. Through environmental pressures, human DNA has mutated such that production of uricase no longer occurs. Fascinating right?

A great example of human genetic changes that were favorable for us as hunter-foragers, but very unfavorable now, when viewed through the lens of longevity.

Gout:

The searing pain of gout may only be comparable to being married for 25 years. When UA crystalizes in joints, the disease gout results. Why some experience gout with relatively low UA levels, and others never get gout despite very high UA levels is a result of small and varied genetic changes called polymorphisms (discussed later).

In general, the risk of gout goes up as UA levels go up. Likewise, lowering UA levels reduce the incidence of gout attacks.

Under a microscope, UA crystals within joints are jagged and sinister looking, thus leading to profound pain and inflammation.

If everyone that had elevated UA contracted gout there would be a massive public health movement. Most medical providers that identify elevated UA levels in the absence of gout ignorantly discount it as asymptomatic hyperuricemia. No gout (happy doctor) but insidious and ongoing metabolic disruption (unhappy/dead patient).

Drivers of UA Formation:

Categorizing the reasons behind elevated UA may be done in three broad ways:

• Over-production (increased cellular turnover; diet).
• Under-excretion (impaired kidney removal of UA).
• Both over-production and under-excretion.

Now for the individual actors…

1) Sugar:

Sugar is toxic in dozens of ways. Add elevated UA to the list.

Recall that sugar is 50% fructose/50% glucose. High fructose corn syrup is, well, higher in fructose, ranging from 55/45 to 65/35.

Fructose is the only carbohydrate that generates the formation of uric acid during metabolism. It is naturally occurring in fruit, agave, honey, and some vegetables, and is extremely sweet.

Unprocessed fructose-containing foods have relatively low amounts of fructose. Depending on the variety, a medium-sized apple contains 5-10 grams of fructose. The fiber and phytonutrients within them cause the fructose to be absorbed slowly, and also counteract the formation of UA (by inhibiting the enzyme xanthine oxidase). Ayoub-Charette et al (BMJ Open. May 2019) looked at over 150,000 people and how they ate and drank. A strong relationship was found between sugar-sweetened beverages and elevated uric acid and gout. No association was found between whole fruit consumption and gout.

High fructose corn syrup (HFCS) is NOT naturally occurring. It is over 50% fructose, and as high as 65%. It was developed in 1957 at Oklahoma State University. Fortunately, it took until the early 70s to make it into our food. In 1984 both Coca-Cola and Pepsi changed from sucrose to HFCS.

HFCS is so biologically active and metabolism-perturbing that finding evidence of Fatty Liver Disease in regular soda drinkers is almost predictable. This includes endurance athletes.

Fructose enters the metabolic pathway called glycolysis after a critical rate-limiting step. This results in cellular depletion of the energy molecule ATP and the production of large amounts of AMP. Through many subsequent steps, AMP is converted to UA.

The glucose piece of sugar elevates blood sugar, spiking insulin and driving the formation of fat. Over time, insulin elevation leads to insulin resistance and eventual Type 2 diabetes. As you will read later, insulin resistance is a potent driver of UA formation.

Thus, both components of sugar, glucose and fructose, drive UA formation through different mechanisms.

2) Alcohol:

Alcohol is metabolized in a similar way as fructose. It uses our primary energy molecule ATP, resulting in AMP which then creates UA.

Alcohol also interferes with the kidney’s ability to remove UA in the urine.

Not all alcohol affects UA formation the same however. Wine, in women, is associated with a decline in UA. In men, there is no measurable effect, which I find entirely unfair.

Beer is particularly bad and represents a double-whammy for UA formation: alcohol, and purines. Although beer contains low amounts of sugar, some varieties are very high in total carbohydrate which may also have an effect on UA elevation.

3) Purines:

Within each of our tens of trillions of cells is genetic material, our DNA. Four nitrogen containing compounds called nucleotides (adenine, guanine, cytosine and thymine) are linked together like words in a sentence creating our unique genome. These sentences are instructions on how to make proteins. Your DNA provides a construction blueprint for protein construction.

Two of these nucleotides, adenine and guanine, are considered “purines”. We make them in our body (endogenous purine source) and eat them (exogenous purine source). The end product of metabolizing these purines is UA and this occurs in our liver, blood vessel lining, and intestines.

Anything that causes tissue damage will result in the liberation of our own purines (see exercise below).

Abundant sources of purines in foods:

• Seafood
• Meats and meat product
• Beer
• Beans
• Vegetables
• Dairy
• Soy

Zgaga et al. (PLOS ONE. 2012) explained that several foods, like cauliflower, spinach, and mushrooms, although purine-rich, are unlikely cause UA elevations. Discussed earlier, Ayoub-Charette et al (BMJ Open. May 2019) found no association between fruit and UA elevations and gout, even though fruit contains fructose. These findings strongly imply that there are other nutrients in fruits and vegetables that reduce UA levels and gout risk, despite having possessing fructose and purines.

Yu et al (Asia Pac J of Clin Nut. 2018) performed a large meta-analysis to determine the relative risk of certain foods causing gout:

Increased risk: Alcohol (158%); fructose (114%); seafood (31%); red meat (29%)

Decreased risk: Dairy (44%); coffee (24%); soy (15%); vegetables (14%)

Interestingly the reduced UA and risk of gout seen with coffee is observed in men only. This makes it even for the wine thing. In women, coffee can actually increase UA slightly, but does not result in increased gout incidence.

The canned advice from most medical providers to patients with gout is to eat a “low purine diet”. I don’t fully agree. If patients with gout ate more anchovies and cut beer and sugar, they’d be leaner, and likely without abdominal obesity and insulin-resistance. Many purine-rich foods are an excellent source of protein and fat. Sugar/fructose, excess carb, and beer should be focused on. And losing weight. Hard to put all that advice in a can though. That would use up the entire four minutes you have with your doctor.

4) Insulin Resistance:

The interplay between insulin and UA is complex. Elevated insulin alone appears not to drive UA formation. Recurrent insulin spikes almost purely caused by high carb and especially sugar consumption invariably lead to insulin resistance.

Insulin resistance occurs when body tissues are bombarded by insulin over time. These tissues will down-regulate (reduce the number of) insulin receptors. Insulin becomes less effective. The pancreas responds by churning out more and more insulin. This process is foundational for the development of metabolic disease.

Recall that one of insulin’s primary functions is allow glucose entry into cells. When blood sugar is high, it literally floods the cell and overwhelms our mitochondria. This leads to mitochondrial damage and oxidative stress.

Oxidative stress is when oxygen free radical formation overwhelms our antioxidant abilities.

There is an emerging hypothesis that insulin resistance is actually an adaptive and protective mechanism. The cells are trying to protect themselves and their mitochondrial components from the toxicity of sugar.

5) Genetics:

Much of our individual characteristics are genetically determined. How we look, how much we weigh, and whether we can dunk a basketball or not is largely attributable to the genetic hand we’ve been dealt. I definitely got aces and eights when it came to jumping ability.

UA levels are also strongly genetically determined.

SLC28A2 is a human gene that codes for the production of a protein in the intestine called CNT2. CNT2 is a transporter protein, allowing passage of dietary purines (see #3 above) into the blood stream.

Zhou et al. (Hereditas. 2019) studied 4000 human subjects and found 8 different versions of the SLC28A2 gene. These different versions are a result of DNA changes called polymorphisms, which we inherit. Some genetic versions allow for enhanced absorption of dietary purines, thus increasing blood purine levels, uric acid production, and gout risk.

There is also huge individual genetic variability in the kidney’s ability to remove UA through the urine. There are two UA transporter proteins in the kidney that reabsorb UA from the urine back into the blood. The genes that produce these two transporter proteins are also subject to genetic variation (polymorphisms) affecting the number and function of these transporters.

6) Vigorous Exercise:

Exercise is good for us, I’m told. I really should try it sometime. Moderate amounts of exercise can actually lower UA levels. There is a threshold however, where the opposite can occur, and vigorous, sustained exercise can elevate UA through numerous mechanisms:

We naturally break down cells in our body every day. This cellular turnover liberates the nucleotides adenine and guanine (purines), which lead to UA formation. Sustained and vigorous exercise can result in cellular damage, turnover, an increase in purines and subsequent UA production.

Lactic acid produced from vigorous exercise impairs UA removal by the kidneys.

The muscle energy source creatine phosphate can become depleted with exercise. This results in increase purine production.

Most people sweat when they exercise. Some profusely. Sweating can lead to relative dehydration and reduced blood volume. This state triggers the release of ADH (anti-diuretic hormone). ADH reduces urination to “save” fluid. With reduced urine volume, less UA is removed from the body.

Human Mammals Biggest Killer:

The actions of XO (xanthine oxidase, the enzyme that makes UA) generate reactive oxygen species (free radicals) as byproducts. This is the fundamental reason UA is thought to harm the cardiovascular system, but there are other mechanisms as well. These include elevated blood pressure, hypertrophy of muscle within the arterial wall, arterial stiffening, and elevated C-reactive protein (CRP). CRP levels correlate with the risk of having a heart attack.

CRP is a normal constituent of our immune system. It increases in response to any inflammatory stimuli, and is a lab test used to look for inflammatory disease. It is also checked in asymptomatic patients to assess the risk of heart disease.

Arterial disease in the heart or elsewhere is driven by inflammation. Many studies have demonstrated the predictive value of CRP for having cardiovascular events.

Ruggiero et al (Am J of Card. July 2007) showed that increases in UA directly predict increases in CRP. Rothenbacher et al (PLOS ONE. 2012) took it a step further and found that elevated UA was actually a better predictor of cardiovascular events than CRP. Furthermore, they suggested that elevated UA independently could be causing these disease processes.

Although the connection between elevated UA and cardiovascular disease (CVD) was first made in 1879, the lack of a clear causal mechanism between UA and CVD has led to this correlation being largely “ignored”, according to Muiesan et al. European Cardiology article in 2016. The familiar question being is this just an observed association or is there causality.

Many studies performed since the 1960’s show an association between CVD and UA at a level of 5 to 5.5. These are levels below recommendations from European and American rheumatology groups, which is <6, which is a little frightening.

In addition, many studies in the last 50 years have supported UA as an independent risk factor for CVD. This is a statistical designation, one of strength, but still does not necessarily mean causality.

There is much as yet that remains unknown about how UA contributes to CVD. What is apparent however is that elevated UA is strongly associated with CVD irrespective of the presence of gout. Lowering your UA levels may very well offer a way to lower relative risk of humans biggest threat to life, CVD.

Uric Acid and Hypertension:

Many authors in many studies correlated elevate UA with elevated blood pressure.

Dr. Rick Johnson (Johnson et al. Scientific America. 2015) of the University of Florida College of Medicine, through animal studies, determined that UA elevates blood pressure two ways:

• Through oxidative stress, resulting in constriction of blood vessels.
• Through direct effects of the kidneys and how they excrete sodium.

What about bigger rats? Yep, Dr. Johnson studied humans too (Johnson et al. JAMA. 2008). 90% of studied individuals with hypertension had elevated UA. Treating them with the UA lowering medication allopurinol brought 85% of patients blood pressure to the normal range, simply by lowering their UA. Maybe the gout medication allopurinol should also be considered a hypertension medication.

As for empiricism…in my clinical experience, hypertension is much harder to control in the setting of elevated UA, commonly requiring 3 or more medications. Lowering UA by some means commonly results in considerable blood pressure improvements with less medication.

Uric Acid and Inflammation:

As I tell patients, inflammation is ideally turned on when we are sick and injured, and then it should be largely turned off. Elevated UA disallows our inflammatory pathways from being shut off. Spiga et al. (Arter, Throb, and Vas Bio. June 2017) reported that inflammation and elevated UA go hand in hand.

Inflammation is a core etiological driver of heart disease, dementia, cancers, diabetes and basically every chronic illness. We are so accustomed to looking at individual chronic diseases as if they have their own unique causation drivers. Slowly the concept of metabolic dysfunction and inflammation as the principal drivers of disease is becoming widely accepted:

If you read Drop Acid by Dr. Perlmutter you would know more about UA and its associated health consequences than the vast majority of medical providers. Dr. Perlmutter states:

It’s also astonishing to think that the same inflammatory strategies our bodies heavily used for millennia to ward off microbial invaders and help heal open wounds could slip beyond our control and leave us chronically inflamed: it’s as if, from an evolutionary perspective, we’ve become victims of our own success.

UA drives inflammation, which was favorable for early humans. It is unfavorable for us now.

The Pandemic Metabolic Syndrome:

Metabolic Syndrome is mainstream. It is widely recognized even among the most metabolically inept physicians. They like it because it’s cookbook. It’s a list of findings. Medical providers like it because it’s tangible, quick, reproducible, easy to identify, and their hand is already on the door knob.

All the steps that should follow identification (diagnosis) however, are pathetically lacking and illustrate the absolute disconnect physicians have between their medical school study of biochemistry, and its application to human metabolic disease.

Let me rephrase this…the list below are manifestations of being metabolically ill, and are easy to identify. It is up to YOU to find out how to fix it.

Many of you have this condition and don’t know. Sugar-fueling, carb-loading, beer-drinking competitive endurance athletes may have it, don’t know it, or don’t care because they feel fit and think that exercise somehow makes them immune to metabolic disease.

This concept that sugar isn’t toxic in those that regularly exercise is pervasive, and represents a level of idiocy that is hard to eclipse.

Metabolic syndrome is a constellation of conditions, comprising 5 key features:

1. High blood pressure.
   
   
2. Elevated blood sugar.
   
   
3. Increased waist circumference (over 40 inches in men and 35 inches in women).
   
   
4. Elevated triglycerides (fat in the blood).
   
   
5. Low HDL (good cholesterol).

Having this condition implies a sick metabolism and increases the risk of heart disease, type 2 diabetes, numerous cancers, dementia, stroke, and other conditions. The risk of dying from infections is also considerably higher in those with Metabolic Syndrome.

So, what about uric acid? UA is so implicated in metabolic dysfunction and driving the individual components of this condition that it is now considered “a new marker for metabolic syndrome” (Billiet et al. Rheumatology 2014).

Simply lowering your UA level can stop the driving of Metabolic Syndrome elements, thus reducing your risk of numerous diseases.

Uric Acid’s Effect on Other Important Chemicals:

-Nitric Oxide:

“NO” is the answer I usually get when suggesting a woman join me for coffee. It also stands for Nitric Oxide.

It doesn’t take a cognitive colossus to know that optimal performance in athletics, or just life, might be more efficiently achieved with increased blood flow to muscles. NO has the ability to “vasodilate” (dilate blood vessels), thus increasing blood, oxygen, and nutrients to working muscle.

NO’s role in insulin function is more recently understood. Wang et al (Diabetes Dec 2013) describes how NO helps insulin function optimally at muscle cells thus allowing the entry of glucose and the formation of glycogen.

A mini summary…NO enhances blood flow to muscle, and improves muscle insulin function, thereby allowing the entry of glucose into muscle cells to create more energy. All of this allows for better running, wood chopping, ladder climbing, sex, yard games, shoveling, hiking, swimming, biking, and sex.

Here’s a news flash: UA compromises NO in two major ways. UA interferes with NO formation, and also, its function. This collectively increases the risk of heart disease, diabetes, and even difficulty with erections. Seriously.

Because human performance (on the road and in the sack) is at stake, it’s important for you to understand this. Insulin, when functioning properly, stimulates the uptake of glucose into muscle and this action is dependent on NO. UA hampers NO. UA formation is driven by fructose. Sugar is half fructose. This represents another one of sugar’s toxicities.

-ATP:

Adenosine triphosphate, ATP, is the energy currency of our body. It is what makes everything work.

ATP is generated by the mitochondria within our cells. For you athletes, lots of ATP generation is critical to performance. With training, we develop enhanced mitochondrial ability to make ATP.

When we consume sugar, the enzyme fructokinase metabolizes the fructose piece. This process uses ATP. Douard et al (J of Phys. Jan 2013) showed that a cellular fructose load, as provided by sugar-sweetened beverages, cause a reduction of ATP by 40-50%. Sugar impairs performance by depleting our primary energy currency.

Recall that when ATP is used, AMP is created. AMP then drives the formation of UA. Are you coming to understand how sugar drives metabolic disease? Uric acid formation is just one of them.

-AMPK and AMPD2:

We’re getting in the biochemical weeds now. Stay with me.

AMPK is adenosine monophosphate-activated protein kinase. It is extremely favorable for a healthy human metabolism. This enzyme, when activated, shifts our metabolism to the burning of fat. It also directs cellular cleaning called autophagy. Activation of AMPK occurs by a healthful diet, some supplements, intermittent fasting, and the medication metformin.

AMPD2 is the opposing enzyme. It is adenosine monophosphate deaminase 2. It increases fat storage.

Studies on hibernating animals (Lanaspa et al. PLOS ONE. April 2015) showed that they increase fat storage, particularly in their livers, by activating AMPD2. When hibernating, they toggle to activation of AMPK to then burn this stored fat. Fascinating right?

Uric acid drives this activation of AMPD2, as it does in humans. Fatty livers, abdominal obesity, and metabolic syndrome are the result. Most humans are biochemically always preparing for “hibernation”.

When we consume sugar, fructose levels spike. Fructose, along with excessive dietary purines (discussed previously) undergo metabolism that yields AMP (adensine monophosphate), the precursor to both AMPK and AMPD2. AMP also triggers the formation of UA, which then signals the AMP to be converted to AMPD2.

Sugar > Fructose > Elevated AMP > Elevated UA > AMPD2 formation > Slow metabolism/fat formation > metabolic disease > human misery and ass-time in medical waiting rooms.

Uric X:

My younger son has an entire piece of furniture, with rope lighting, to house his knife collection. Most of which I’ve given him, from my robust collection. Several knives are of the fixed-blade variety, for bushcrafting.

Each knife has its respective strengths, but are uniformly deficient. That’s why I designed my own.

It’s the same with UA-lowering supplements, of which there are several. I have reviewed their formulations, and in many cases their effects on human subjects (i.e. my patients). I very much wanted to find an effective non-pharmacological modality for patients to lower their UA but did not find one that made sense from a formulation perspective, or that was effective.

For three years, I’ve studied the biochemistry and evidence behind individual UA lowering compounds. I’ve come to understand them, their dosages, and synergy between them.

The result is Uric X. Here is what it consists of and why I picked them:

1) VITAMIN C (VC)

There is strong evidence that 500 mg daily significantly lowers UA levels.

VC plays myriad beneficial biological functions for humans. Its most prominent role involves antioxidation. Humans are unable to synthesize VC, and it must be consumed/supplemented.

Multiple large well-conducted human trials observe a significant reduction in serum uric acid at a daily dose of 500 mg. No compelling evidence was found that doses higher than 500mg resulted in any notable incremental benefit.

A meta-analysis summarizing results of over 1,000 human subjects concluded Vitamin C supplementation significantly lowers serum uric acid (Liu et al. Complement Ther Med. 2021).

A study of 1387 men found Vitamin C 400-500 mg orally daily had a significant effect on lowering serum uric acid (Gao et al. J Rheumatol. 2008).

In a study of 172 patients on only 250 mg of VC 3 times per week, the average UA level of 6.4 improved to 5.8 (Biniaz et al. Iran J Kidney Dis. 2014).

Another meta-analysis of 2082 published studies reported on the significant effect of vitamin C supplementation on lowering serum uric acid (Juraschek et al. Arthritis Care Res. 2011).

A randomized clinical trial involving 184 human subjects found that uric acid was lowered by an average of -0.5 mg/dL in the participants who took Vitamin C 500 mg daily (Huang et al. Athritis Rheum. 2005).

Linani et al. published a fascinating study in 2022 testing the inhibitory effects of vitamin C (and folic acid, discussed below) on xanthine oxidase. It concluded that vitamin C (and folic acid) was a potent xanthine oxidase inhibitor and displayed better inhibition of this enzyme than the pharmaceutical drug Uricase (Linani et al. Chem Biol Interact. 2022).

A huge study of over 106,000 patients correlated higher blood levels of VC with lower blood levels of UA (Kobylecki et al. Rheumatol. 2018).

A meta-analysis study published in 2011 pooled 13 randomized controlled trials looking at VC supplementation and UA levels. The investigators conclusion was: “In aggregate, vitamin C supplementation significantly lowers serum uric acid” (Juaschek et al. Arthritis Care Res. 2011).

VC effects on UA and gout risk is multiple. The most prominent role appears to be its uricosuric effect. Known for decades, VC impairs the kidney’s ability to reabsorb UA. This results in more UA being eliminated from the body through urination (Stein et al. Ann. Intern. Med. 1976).

More recently, a specific anti-inflammatory pathway of VC has been discovered. UA triggers the inflammatory protein TXNIP, which is converted to another inflammatory chemical NLRP3. VC inhibits the formation of NLRP3 (Kim et al. Biochem. Biophys. Res. Commun. 2019).

2) LUTEOLIN

There is strong evidence that 200 mg daily significantly lowers UA.

Luteolin is a flavonoid (a pigment nutrient in plants with widespread health benefits). Like other flavonoids it is able to bind to xanthine oxidase, and inhibit it. There is good evidence that it is likely the most potent flavonoid at reducing UA formation.

A well-done mouse study identified the physiological mechanisms by which luteolin possesses potent uric acid-lowering, antioxidant bioactivities and xanthine oxidase inhibition (Yu et al. Food Sci Nutr. 2024).

A recent mammalian (rat) study demonstrated 138 key targets of uric acid metabolism targeted by a complement of flavonoids, including luteolin. Enhancement of the enzyme superoxide dismutase (a powerful detoxification and free radical quenching enzyme) and robust suppression of multiple inflammatory mediators including IL1B, IL6, TNFα, ICAM1, VCAM1, TGFβ1, and NF-κB were also demonstrated. Furthermore, this study found that flavonoids inhibited xanthine oxidase activity, and enhanced uric acid excretion through the kidneys (Liang et al. Sci Rep. 2024).

There are multiple biochemistry and food chemistry in vitro studies (in-lab studies, not on mammals) that demonstrate the biochemical interaction of luteolin with the xanthine oxidase enzyme. The studies all found that luteolin binds directly with the primary amino acids located within the active enzymatic site pocket of XO (which is molybdenum dependent). These studies suggest synergy between molybdenum (discussed below) and luteolin (Yan et al. Food Chem. 2016; Balazs et al. Biomed Pharmacother. 2023).

Another study evaluated the activity of the xanthine oxidase enzyme and found that flavonoids, including luteolin inhibited xanthine oxidase activity even at low concentrations (Nagao et al. Biosci Biotechnol Biochem. 1999).

Mohos et al. found that numerous flavonoids, including luteolin proved to be strong inhibitors of XO. This inhibition was similar or stronger than that of the medication allopurinol (Mohos et al. Int J Mol Sci. 2020).

A study by Gan et al. found excellent inhibition of xanthine oxidase by celery seed extracts, which were found to contain multiple different luteolin types (Gan et al. Molecules. 2023).

3) MOLYBDENUM (Mo)

There is strong evidence that 50 mcg daily significantly lowers UA.

Mo is an essential trace mineral. Humans cannot synthesize it and it must be consumed. It plays many vital roles in human physiology. Its effects on UA metabolism are varied and involve kidney elimination of UA, inhibition of xanthine oxidase, and also through inflammatory modulation.

A large NHANES study of 15,370 adults showed a relationship between Mo levels and the amount of UA excreted through the kidneys. This finding then correlated with decreased blood UA and a lower incidence of gout. Higher Mo levels also correlated with lower C-reactive protein (CRP) levels, implying less systemic inflammation (Joun et al. Plos One. 2024).

An animal study found lowered values of serum UA in animals receiving 400 mcg supplementation of Mo daily (Karring et al. Acta Vet Scand. 1981).

A biochemical study reported on the specific binding site on xanthine oxidase through which Mo interacts (Novotny. Adv Nutr. 2018).

There are multiple biochemistry and food chemistry in vitro studies (in-lab studies, not on mammals) that demonstrate the biochemical interaction of luteolin with the xanthine oxidase enzyme. The studies all found that luteolin binds directly with the primary amino acids located within the active enzymatic site pocket of XO. This binding is molybdenum dependent (Yan et al. Food Chem. 2016; Balazs et al. Biomed Pharmacother. 2023). Synergy thus exists between luteolin and Mo.

4) Methyl-FOLATE

There is strong evidence that 800 mcg daily significantly lowers UA levels.

Folate is a vitamin, also known as B9. It serves many vitals roles in human physiology including synthesis of DNA, formation of red blood cells, proper neural development, homocysteine break down, and UA lowering.

In the body, folate needs to be converted to more biologically active forms through a process called methylation. 25% of Hispanics and 10% of Caucasians have significant mutations (MTHFR polymorphism) disallowing this conversion (Pietrzik et al. Clin. Pharmacokenet. 2010). Because of this, folate in Uric Rx is in a pre-methylated form.

Two different analyses of a large study of 15,364 Chinese adults study found that a small dose of folic acid (800 mcg) significantly reduced UA. Folic acid is a potent inhibitors of xanthine oxidase, with apparent inhibition comparable to that of the medication allopurinol (Scheepers et al. Am J Clin Nutr. 2017; Qin et al. Am J Clin Nutr. 2017).

A meta-analysis of human studies found that folic acid was effective for lowering uric acid in the blood (Singh et al. Biotechnol Appl Biochem. 2019). A mammalian study (mice) found that folic acid decreased kidney tissue injury and enhanced kidney excretion of UA. Furthermore, folic acid was shown to lower a few different drivers of inflammation (Wang et al. J Agric Food Chem. 2022).

A small human study found a 10% reduction in uric acid excretion within 1 week of beginning folic acid (Flouvier et al. Ann Intern Med. 1978).

A mammalian study (rats) found folic acid lowered blood UA by inhibiting uric acid synthesis and stimulating uric acid excretion in part by modulating the gut microbiota. Its conclusion was that folic acid is effective and safe as a therapeutic agent to improve elevated UA levels (Sun et al. Front Microbiol. 2022).

Another mammalian (rat) study found that that folic acid reversed kidney damage from high UA by two distinct mechanisms (Wu et al. Mol Med Rep. 2016).

Another study tested the inhibitory effects of folic acid on xanthine oxidase. It concluded that folic acid was a potent xanthine oxidase inhibitor and displayed better inhibition than the pharmaceutical drug Uricase (Linani et al. Chem Biol Interact. 2022).

5) CELERY SEED EXTRACT (CSE)

There is strong evidence that 300 mg daily significantly lowers UA levels.

Apium graveolens is a naturally occurring flowering plant. It is widely cultivated and recognized as celery. CSE is a concentrated form of compounds derived from celery seeds. These compounds, known as flavonoids, collectively and individually exert many beneficial biological effects on human physiology, including UA lowering and ant-inflammation. Luteolin described above is one of these flavonoids. CSE contains many others.

A recent mammalian (rat) study demonstrated 138 key targets of uric acid metabolism targeted by a complement of flavonoids. Enhancement of the enzyme superoxide dismutase (a powerful detoxification and free radical quenching enzyme) and robust suppression of multiple inflammatory mediators including IL1B, IL6, TNFα, ICAM1, VCAM1, TGFβ1, and NF-κB were also demonstrated. Furthermore, this study found that flavonoids inhibited xanthine oxidase activity, and enhanced uric acid excretion through the kidneys (Liang et al. Sci Rep. 2024).

Another in vitro study evaluated the activity of the xanthine oxidase enzyme and found that flavonoids inhibited xanthine oxidase activity even at low concentrations (Nagao et al. Biosci Biotechnol Biochem.1999).

Mohos et al. found that numerous flavonoids proved to be strong inhibitors of XO. This inhibition was similar or stronger than that of the medication allopurinol (Mohos et al. Int J Mol Sci. 2020).

Another study found excellent inhibition of xanthine oxidase by celery seed extracts, which were found to contain multiple different luteolin sub-types (Gan et al. Molecules. 2023).

Uric X Summary:

Other supplements and compounds were studied. Tart cherry extract was deemed not expected to perform at doses that could fit in capsules. As a xanthine oxidase inhibiting flavonoid, luteolin is considered superior to quercetin and green tea extracts.

After extensive study over three years, coupled with many years of empiric clinical observations, the following FIVE components are felt to perform the best at lowering uric acid, and minimizing metabolic risk. Uric Rx is thus comprised of:

1) Vitamin C, 500 mg daily.
2) Luteolin, 200 mg daily.
3) Molybdenum, 50 mcg daily.
4) Methyl-folate 800 mcg daily.
5) Celery Seed Extract, 300 mg daily.

Conclusion:

I want to implore you to embrace the concept of not waiting, and advocating for yourself. It’s the rare provider that’s equipped to guide you in a healthful way, as they understand very little about metabolism, UA, and how it drives disease. It’s not their fault, it’s the system they operate in. And it’s their fault.

Here’s a summary of action items that can be implemented now:

1. Come to understand UA. Through this article, the book Drop Acid, and other means.
   
   
2. Check your UA levels. Preferably in a fasting state and without vigorous exercise in the few days preceding the blood draw.
   
   
3. Eat sugar on rare occasions, in small amounts, and with mindfulness. Next to never drink sugar, or fructose and do not fuel with it for exercise.
   
   
4. Reduce your UA to below 5. Uric X, along with dietary improvements, is designed to do this.

There is strong evidence that lower UA levels confer a lower risk of developing metabolic disease, including the biggest threat to life, cardiovascular disease.

There is a strong genetic component to elevated UA levels and subsequent risk. A genetic contribution, with excessive exercise, alcohol consumption, and especially regular sugar consumption is a potent combination for insidious changes that result in disease.

Embark on the change you wish to take place. Your individual health is of paramount importance. Not just for you, but those that rely on you. Knowing your UA levels, and reducing it can lower disease risk over time. Although your genome is not modifiable, your action is.