Tetrahydrobiopterin, also known as BH4, is essential for many processes in the body. It helps with the heart, brain, and the digestive and reproductive systems. Supplements can help prevent many disorders.
What is Tetrahydrobiopterin (BH4)?
Tetrahydrobiopterin (BH4), also known as sapropterin (INN), plays a key role in a number of physiological processes. It is involved in the formation of neurotransmitters, heart and endothelial dysfunction, the immune response, and pain sensitivity .
BH4 is essential for the action of several enzymes, including ones responsible for neurotransmitter synthesis, host defense, and formation of lipids .
Reduction in vascular BH4 bioavailability is a central mechanism for the development of impaired NO-mediated microvascular (smaller blood vessels) function in a wide variety of conditions, including diabetes, hypertension, hypercholesterolemia, atherosclerosis, and aging .
Tetrahydrobiopterin has clinical trials on autism, ADHD, hypertension, endothelial dysfunction, and chronic kidney disease .
The aforementioned disorders also are associated with elevated vascular oxidative stress, and BH4 is particularly susceptible to oxidation by peroxynitrite (ONOO−), a reactive oxygen species byproduct of the NO and superoxide anion (O2−) reaction.
Oxidation of BH4results in promoting the transfer of electrons to molecular oxygen resulting in the production of Superoxide rather than Nitric Oxide.
One hypothesis is that exogenously administered BH4 is oxidized rapidly to BH2 upon entering circulation, diffuses into the cell as BH2, and then is recycled back to BH4 via the “salvage” pathway enzyme DHFR.
My Experience With BH4 – One That I Recommend
BH4 puts me in a Zen state that can be characterized as a calm/relaxed alertness. It certainly has mood-boosting properties and I enjoy taking it. Since I don’t have any condition that is benefited by it and I don’t have anxiety or depression, the benefits to me are small. Since it is expensive, it’s not a regular tool in my arsenal, but it’s a good product to try to see how it makes you feel.
Health Benefits of Tetrahydrobiopterin
1) Prevents Heart Failure
Nitric oxide synthases (NOS) needs BH4 for the production of nitric oxide. When there is low BH4 concentration, NOS generates superoxide instead of NO, which increases oxidative stress and causes endothelial dysfunction [5, 6].
Oxidative stress can contribute to many complications, such as heart disease, high cholesterol, diabetes, high blood pressure, and stroke. Supplementation with BH4 may restore BH4 concentrations and prevent these diseases .
A single oral therapeutic dose of a synthetic BH4 improved reflex skin vasodilation during whole-body heat stress by augmenting NO-mediated dilation.
Blood flow restriction (ischemia) decreased cardiac BH4 content by 85, 95, or 97% after 30, 45, or 60 min of ischemia, respectively. Paralleling the decreases in BH4, reductions of eNOS activity were seen of 58, 86, or 92% and NOS-derived superoxide production were greatly increased .
Thus, BH4 depletion contributes to postischemic eNOS dysfunction, and BH4 treatment is effective in partial restoration of endothelium-dependent coronary flow.
Supplementation of BH4 may, therefore, be an important therapeutic approach to reverse endothelial dysfunction in postischemic tissues .
2) Has Antidepressant Activity
Depression is associated with an inflammatory response as well as activation of the anti-inflammatory reflex system. It is also accompanied by oxidative and nitrosative stress .
The depletion of BH4 reduces the synthesis of neurotransmitters like serotonin, melatonin, dopamine, norepinephrine, and epinephrine. These compounds are essential for controlling daily body functions including mood, sleep cycle, memory, and appetite .
Loss of BH4 might explain some of the symptoms of depression. If BH4 levels increased, then it can be an effective treatment for depression .
3) Might Improve Autistic Symptoms
Levels of BH4 in cerebrospinal fluid are 42% lower in children with Autism Spectrum Disorder (ASD) .
It is possible that metabolic pathways that need BH4 are dysfunctional in children with ASD. Children with ASD can have excessive inflammation, excessive oxidative damage, and overactivation of the immune system, which also reduces BH4 levels [16, 17].
This suggests that BH4 supplementation might improve ASD pathology. BH4 treatment might improve specific autistic symptoms including adaptability, verbal expression, social responsiveness and interactions, communication, cognitive abilities, hyperactivity, and inappropriate speech [18, 19, 20, 21, 22].
4) Helps Treat Diabetes
Diabetes is characterized by glucose intolerance and insulin resistance, which can be caused by endothelial nitric oxide synthase (eNOS) dysfunction. Diabetes can also cause gastroparesis, and its symptoms include pain, nausea, and vomiting [23, 24].
BH4 helps regulate eNOS activity and prevents it from dysfunction. Administration of BH4 in mice lead to less glucose intolerance and insulin resistance; it has the potential to help alleviate symptoms of diabetes [23, 24].
5) Supports Digestive System Function
In mice, BH4 supplementation can help bring serotonin levels back to normal and steady digestive function .
6) Can Help Prevent Problems During Pregnancy
During pregnancy, the maternal blood total cholesterol levels increase in order to ensure normal development of the baby. However, cholesterol levels can exceed normal levels and cause maternal supraphysiological hypercholesterolemia (MSPH), which leads to hardening of the arteries .
Since maternal cholesterol can pass through the fetal barrier to the developing fetus, MSPH can have serious consequences including the development of hardening of the arteries during childhood and later in life [26, 27].
BH4 supplementation could improve BH4 levels and NOS activity hence preventing the potential consequences in the health of the newborn and in its adulthood .
7) Can Prevent Phenylketonuria
Tetrahydrobiopterin deficiency can cause excess phenylalanine concentration, or phenylketonuria (PKU). PKU can cause severe brain damage, mental retardation, seizures, and other abnormalities .
Side Effects and Interactions
No interaction studies have been conducted. Because of its mechanism, tetrahydrobiopterin might interact with dihydrofolate reductase inhibitors like methotrexate and trimethoprim, and NO-enhancing drugs like nitroglycerin, molsidomine, minoxidil, and PDE5 inhibitors. Combination of tetrahydrobiopterin with levodopa can lead to increased excitability.
The effects of oral administration of BH4 are dose-dependent and further studies are required to investigate its long-term effects .
Additionally, the combination of BH4 with other antioxidant compounds is not yet tested .
What Increases BH4
- Exercise (Strenuous) 
- Sauna (hypothesis) 
- Folate/Methyl folate (by scavenging peroxynitrite and increasing recycling) .
- Vitamin C [37, 38]
- Statins /HMG-CoA reductase inhibitors 
- Interferon-gamma (Th1 cytokine) 
- Chronic Pain .
What Decreases BH4
- Defects in the MTHFR gene
- Defects in the DHFR gene
- Defects in the GCH1 gene
- Defects in the SPR gene
- Defects in the GCHFR gene
- Sun/UV .
- Peroxynitrite (oxidative stress)
- Hydrogen peroxide (oxidative stress) 
- Methotrexate (by inhibiting DHFR)
Any advantage of going straight for BH4 versus trying to get there through improved methylation?
People have different blockages for BH4, as discussed above. Some people might do perfectly fine on jumethyl folate, while others will need the real thing.
If you take it, will it stop your natural production of it?
Probably not by that much, but surely to some degree. When you stop taking it, production should resume to normal.
Biosynthesis and Genetics of Low BH4
There are a variety of genes that can cause lower BH4. You must get your genetics tested and sign up to SelfDecode to see if you have SNPs that are not as effective in these genes.
The first step is the conversion of GTP (guanosine triphosphate) to dihydroneopterin triphosphate via the GCH1 gene.
Dihydroneopterin triphosphate and magnesium are then converted to 6-pyruvoyl-tetrahydropterin via the PTS gene. Dihydroneopterin triphosphate can also degrade into neopterin.
6-pyruvoyl-tetrahydropterin and NADPH are converted to tetrahydrobiopterin (BH4) and NADP via the SPR gene. 6-pyruvoyl-tetrahydropterin can also degrade sepiapterin and then dihydrobiopterin (BH2).
Dihydrobiopterin (BH2) and folate also convert to tetrahydrobiopterin (BH4) via the DHFR gene.
The GCHFR gene acts as a feedback mechanism for GCH1 activity. GCHFR normally inhibits GCH1, but in the presence of phenylalanine, it stimulates GCH1.
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