BH4 / Tetrahydrobiopterin / Sapropterin

BH4

BH4, or tetrahydrobiopterin, is used for many imperative and fundamental processes in the body. I will use BH4, tetrahydrobiopterin and sapropterin interchangeably.

 
 

Basics

 
If BH4 is low, you may look like this guy.

If BH4 is low, you may look like this guy.

 

BH4 is a naturally occurring essential cofactor of the three aromatic amino acid hydroxlase enzymes used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters Serotonin, melatonin, dopamine, norepinephrine, epinephrine, and is a cofactor for the production of nitric oxide by the nitric oxide synthases. R

BH4 plays a key role in

  • maintaining a healthy heart, endothelial dysfunction, the immune response and pain sensitivity. R
  • host defense and the formation of lipids. R
  • diabetes, hypertension, hypercholesterolemia, atherosclerosis, and aging. R
  • Autism, ADHD, hypertensions, endothelial dysfunction, and chronic kidney disease (by ONOO and lack of BH4 creating SO instead of NO). R

BH4 is being used in clinical trials to treat autism, ADHD, hypertensions, endothelial dysfunction, and chronic kidney disease. R

Benefits

1. BH4 Reverses PKU

 
Pathophysiology of phenylketonuria, which is due to the absence of functional phenylalanine hydroxylase (classical subtype) or functional enzymes for the recycling of tetrahydrobiopterin (new variant subtype) utilized in the first step of the metabolic pathway.

Pathophysiology of phenylketonuria, which is due to the absence of functional phenylalanine hydroxylase (classical subtype) or functional enzymes for the recycling of tetrahydrobiopterin (new variant subtype) utilized in the first step of the metabolic pathway.

 

BH4 deficiency can cause phenylketonuria, which is the buildup of excess phenylalanine in the body. This can cause severe brain damage, mental retardation, seizures, and other abnormalities. R

BH4 may help lower phenylalanine levels in some people with phenylketonuria. It is FDA approved for this use along with dietary measures. R

BH4 can normalize phenylalanine levels. R R

Treatment with BH4 has better outcomes in earlier stages. R R

2. BH4 May Treat Diabetes

Glucose intolerance, insulin resistance, and gastroparesis are common in diabetes. This can be caused by a dysfunciton in endothelial nitric oxide synthase or eNOS.  BH4 has a glucose-lowering effect. R BH4 can help gastroparesis. R

BH4 leads to less glucose intorance and insulin resistance and has the potential to alleviate symptoms of diabetes. R R

3. BH4 May Treat Autism

 
BH4 supplementation might improve ASD pathology

BH4 supplementation might improve ASD pathology

 

BH4 may improve autistic symptoms such as adaptability, verbal expression, social responsiveness and interactions, communication, cognitive abilities, hyperactivity, and inappropriate speech. R R R R R

Cerebrospinal fluid BH4 levels are 42% lower in children with Autism. R

Metabolic pathways may be dysfunction in children with Autism. Excessive inflammation, excessive oxidative damage, and overactivation of the immune system can reduce BH4 levels. R R

4. BH4 Helps the Heart

NOS (nitric oxide synthases) uses BH4 to create NO (nitric oxide). When BH4 is low, NOS generates superoxide instead of NO. This creates more oxidative stress and can cause endothelial dysfunction. R R  

Heart disease, high cholesterol, diabetes, high blood pressure and stroke all have high levels of oxidative stress. BH4 may help reduce the oxidative stress and prevent these complications. R

BH4 may help with high cholesterol, type 2 diabetes, congestive heart failure and heart disease by restoring proper function of the heart. R R R

BH4 improved reflex skin vasodilation during whole body heat stress. It augmented NO-mediated dilation. This was with one single oral dose. R

Ischemia (blood flow restriction) reduces BH4 in the heart by 85-87% after 30-60 minutes of ischemia. There was also a reduction of eNOS activity from 58-92% and superoxide increased significantly. R

Bh4 can help endothelium-dependent coronary flow, since depletion of BH4 can contribute to postischemic eNOS dysfunction. R


Chronic BH4 treatment has been shown to reduce angiotensin-II-induced hypertension and endothelial dysfunction  and to decrease blood pressure while improving endothelial-dependent relaxation in SHR rats. R R R

5. BH4 Has Antidepressant Effects

 
 

This rabbit is my antidepressant.

Inflammation is closely related to depression and accompanied by oxidative and nitrosative stress. R

High amounts of inflammation and oxidative stress and deplete BH4. R R

BH4 is necessary in the production of neurotransmitters like serotonin, melatonin, dopamine, norepinephrine, and epinephrine, which help with body functions such as mood, sleep cycle, memory and appetite. If BH4 is low then it is possible for neurotransmitters to be low. This may trigger symptoms of depression, thus supplementing BH4 could help relieve depression. R R

6. BH4 Can Assist in Pregnancy

 
 

Accurate representation of pregnancy

Blood cholesterol levels increase during pregnancy. This is normal. The high levels of cholesterol can cause MSPH (maternal supraphysiological hypercholesterolemia. This can lead to the hardening of arteries. R MSPH can have serious consequences to the child later in life, since cholesterol can pass through the fetal barrier. R R

BH4 and NOS activity are reduced in MSPH, especially in the human umbilical vein. R R

BH4 treatment could prevent the potential consequences MSPH has on the newborn child by improving NOS activity and BH4 levels. R

7. BH4 Helps the Digestive System

Serotonin is essential for the digestive system to work. BH4 is essential to make serotonin. R 

BH4 supplementation can restore serotonin back to normal levels in mice, thus helping regulate digestive function. R

8. BH4 May Help the Liver and Hyperammonia

Dysbiosis can cause hyperammonia. R

Gut-derived ammonia is taken up by the liver and consumed in the urea cycle. By creating portosystemic shunts, cirrhosis allows absorbed ammonia to escape hepatic metabolism, increasing blood ammonia, which contributes to the pathogenesis of hepatic encephalopathy and can be neurotoxic. R

NOx levels are correlated with the presence and severity of HE. NOx levels determination, in addition to ammonia levels, could contribute in diagnosis of HE. R

Supplementation with BH4, L-Arginine and Vitamin C may act synergistically to decrease oxidative stress, increase nitric oxide and improve blood flow. R

9. BH4 May Help with MCAD

Mast cell activation disorder (MCAD) is an immunological condition in which mast cells inappropriately and excessively release chemical mediators, resulting in a range of chronic symptoms, sometimes including anaphylaxis or near-anaphylaxis attacks. R

Mast cells (MC) are biologically potent, ubiquitously distributed immune cells with fundamental roles in host integrity and disease. MC diversity and function is regulated by exogenous nitric oxide; however, the production and function of endogenously produced NO in MC is enigmatic. R

NO formation inhibits MC degranulation. R BH4 is essential to synthesize NO. R

10. BH4 May Improve Rheumatoid Arthritis

Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. R

 This result suggests that BH4 supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. R

My Experience with BH4

My blood results showed my ammonia as being high. I had been on Amy Yasko's BH4/Liver Support for a bit, along with taking L-Citruline, until I ordered some BH4 to try. I have had everything to signify low BH4: high ammonia, dysbiosis, and homozygous mutation in the A1298c gene. 

When I first tried BH4, I used it with Tyrosine. Since tyrosine is the precursor to L-Dopa, which can convert into dopamine, I figured BH4 as a cofactor to the neurotransmitter production would help.

I noticed an increase in energy and a feeling of tranquility/peacefullness. Unfortunately, because of the side effects (as you can see in the video), I only now take it once or every other a week (2.5mg) to support ammonia detox. I have about 150mg stored in my freezer.

I've noticed if I take it more than once a week, I wake up a lot earlier ~4:30am, no matter when I go to sleep.

Side Effects

I noticed one very important side effect. I essentially had insomnia from it. I would sleep fine for a couple hours then wake up very early. I would be refreshed, but I don't believe that is sustainable. 

I was concerned that taking BH4 would downregulate your natural production on it. I asked around on Reddit and asked Joseph Cohen, but unfortunately, could not find a clear answer.

Other side effects can include headaches, runny nose, diarrhea, and vomiting. R 

Dosing

I take 2.5mg once a week. 

For PKU 200mg is necessary and is usually prescribed as Kuvan by Biomarin.

Amy Yasko recommends, "Pharmacological doses (200 mg/day) of BH4 has been shown to be safe and effective when used to treat endothelial dysfunction in hyperlipidemic individuals, and in dealing with Methyl Cycle defects, far lower nutritional doses (2.5 mg two times a day) are typically employed, but here a little bit of BH4 can go a long way."

James Roberts recommends, "Low daily doses of BH4 (1.25 mg) initially appear to stimulate detoxification over the first several weeks of use. After this initial detoxification effect, the BH4 appears to have a very positive impact on language for individuals with CBS C699T+ mutations. It seems it is possible to restore BH4 stores through supplementation."

Storage

BH4 is highly unstable when exposed to air and heat. It is necessary to store it in a refrigerator or freezer. The BH4 from irc.bio has been mixed with Vitamin C, to prevent oxidization. 

Mechanism Of Action

 
Intracellular 5,6,7,8-tetrahydrobiopterin (BH4), synthesis, oxidation, and recycling in endothelial cells. GTP, guanidine triphosphate; GTPCHI, GTP cyclohydrolase I; PTPS, pyruvoyl tetrahydrobiopterin synthase; SR, sepiapterin reductase; DHFR, dihydrofolate reductase; ˙NO, nitric oxide; O2·−, superoxide anion radical; ONOO−, peroxynitrite; H202, hydrogen peroxide; BH3˙, trihydrobiopterin radical; DHF, dihydrofolate; 5MTHF, 5-methyltetrahydofolate; eNOS, endothelial nitric oxide synthase; Asc, ascorbate; Asc˙−, ascorbate radical.

Intracellular 5,6,7,8-tetrahydrobiopterin (BH4), synthesis, oxidation, and recycling in endothelial cells. GTP, guanidine triphosphate; GTPCHI, GTP cyclohydrolase I; PTPS, pyruvoyl tetrahydrobiopterin synthase; SR, sepiapterin reductase; DHFR, dihydrofolate reductase; ˙NO, nitric oxide; O2·−, superoxide anion radical; ONOO, peroxynitrite; H202, hydrogen peroxide; BH3˙, trihydrobiopterin radical; DHF, dihydrofolate; 5MTHF, 5-methyltetrahydofolate; eNOS, endothelial nitric oxide synthase; Asc, ascorbate; Asc˙−, ascorbate radical.

 

Here is a summary of the BH4-related biochemical transformations: R

  • Phenylalanine hydroxylase (PAH) enzyme to convert Phenylalanine (PHE) to Tyrosine (TYR)
  • Tyrosine hydroxylase (TH) enzyme to convert Tyrosine to L-DOPA (DOPA)
  • Tryptophan hydroxylase (TPH) enzyme to convert Tryptophan to 5-Hydroxytryptophan (5-HTP)
  • Nitric oxide synthase (NOS) enzyme to convert a Arginine (ARG) to Nitric oxide (NO)

The enzyme DHFR may recycle BH2 into BH4. This would be after exogenously administered BH4 has been oxidized into BH2. R

Nitric Oxide Production

BH4 is important for nitric oxide synthases and when it is missing, enzymes become "uncoupled". This uncoupling produces Reactive Oxygen Species (ROS) rather than NO. 

Genetics for Low BH4

 
If your parents are heterozygous, you have a 1-in-4 chance.

If your parents are heterozygous, you have a 1-in-4 chance.

 

Defects in these genes can predispose you to low BH4 production.

  • MTHFR A1298C is involved in converting 5-methylfolate (5MTHF) to tetrahydrofolate (THF). A1298C helps generate BH4. R
  • CBS catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine. BH4 can also become depleted with a CBS upregulation. R
  • DHFR encodes an enzyme that plays a part in folate metabolism. R R
  • GCH1 encodes an enzyme called GTP cyclohydrolase 1. It helps produce BH4. R
  • SPR provides instructions for making the sepiapterin reductase enzyme, which is involved in the last of three steps of producing BH4. R
  • GCHFR binds to and mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase I. R
  • PTS facilitates folate biosynthesis. A mutation in this gene could directly cause BH4 deficiency. R
  • QDPR produces the enzyme quinoid dihydropteridine reductase. This enzyme is part of the pathway that recycles BH4. R

Biosynthesis for Low BH4

 
 

GTP (guanosine triphosphate) converts into dihydroneopterin tiphosphate (GCH1 gene). Dihydroneopterin triphosphate and magnesium convert into 6-pyruvoyl-tetrahydropterin vita (PTS gene). Dihydroneopterin triphosphate can degrade into neopterin. 

6-pyruvoyl-tetrahydropterin and NADPH convert into BH4 and NADP (SPR gene). 6-pyruvoyl-tetrahydropterin can also degrade to sepiapterin and then BH2. BH2 and folate convert to BH4 (DHFR gene). GCHFR can be a feedback mechanism for GCH1 activity. GCHFR will inhibit GCH1, but if phenylalanine is present, it will stimulate GCH1.

Tests

  1. 23andMe - then put your raw data into Promethease
  2. Neopterin/Biopterin Profile (Urine)

Where to Buy BH4

Irc.bio - Here is the best source I know, unless you can get a prescription for Kuvan.

Ways to Increase It

 
Statins can be good and bad.

Statins can be good and bad.

 
 
Pain induces the upregulation of GTP cyclohydrolase (GCH1), an early rate-limiting step in the synthesis of tetrahydrobiopterin (BH4). BH4 modulates several enzymes, including neuronal nitric oxide synthase (nNOS), which generates nitric oxide (NO), and aromatic amino acid hydrolase, which is involved in the synthesis of the catecholamines and serotonin. nNOS is also under the control of NMDA (N-methyl-D-aspartate) receptors through their regulation of intracellular calcium ions.

Pain induces the upregulation of GTP cyclohydrolase (GCH1), an early rate-limiting step in the synthesis of tetrahydrobiopterin (BH4). BH4 modulates several enzymes, including neuronal nitric oxide synthase (nNOS), which generates nitric oxide (NO), and aromatic amino acid hydrolase, which is involved in the synthesis of the catecholamines and serotonin. nNOS is also under the control of NMDA (N-methyl-D-aspartate) receptors through their regulation of intracellular calcium ions.

 

Ways to Decrease It

  • The mutations listed above R
  • Methotrexate, which inhibits DHFR R
  • Sun/UV R
  • Inflammation R R
  • Overactivation of the immune system R R
  • Oxidative Stress/Damage R R  R
  • Hydrogen peroxide R
  • Peroxynitrite R
  • High protein diet R R
  • Hyperammonia R
  • Heavy metals such as Mercury, Lead, Aluminum and Iron R R

More Research

  • The production, salvage and regeneration of BH4 involve the action of a series of enzymes: R R R
    • GTP cyclohydrolase I (GTPCH)
    • 6-pyruvoyltetrahydropterin synthase (PTPS)
    • sepiapterin reductase (SR)
    • dihydrofolate reductase (DHFR)
    • pterin-4a-carbinolamine dehydratase (PCD)
    • dihydropteridine reductase (DHPR) 
  • BH4 stabilizes and donates electrons to the ferrous-dioygen complex in the oxygenase domain, as the initiating step of L–arginine oxidation in invitro experiments. R
  • A functional role for the stimulation of tetrahydrobiopterin biosynthesis by cytokines is the formation of a limiting cofactor required for the enzymatic conversion of L-arginine to citrulline and nitric oxide. R
  • Eight of 23 patients with acute cerebellar ataxia (ACA) following Epstein-Barr virus (EBV) infection -  All had a novel mutation in the tetrahydrobiopterin pathway involving sepiapterin reductase, with autosomal recessive inheritance. R
  • Tetrahydrobiopterin (BH4): Its Role in the Body and Where to Buy It R