The previous article, Could Testosterone and Estrogen Issues Be Related to Imbalanced Sulfur Metabolism?. discussed how excess hydrogen sulfide can affect estrogen signaling and sulfite can lower testosterone production. The effects of these two sulfur-containing molecules extend far beyond sex hormones, potentially causing a wide variety of symptoms, including anxiety, depression, obsessive-compulsive tendencies, muscle tension, Mast Cell Activation Syndrome, diarrhea or excessive gut motility, reduced energy production, insomnia, and more.
How Excess Sulfite Affects Energy Production, Neurotransmitter Production, Mental Health, Muscles, Pain, and Sleep
Sulfite is directly neurotoxic (R), and when sulfite accumulates it also combines with the amino acid cystine to form S-sulfocysteine, an excitatory neurotransmitter that is an analog of glutamate and activates NMDA receptors. Based on what is known about the NMDA receptor, elevated S-sulfocysteine could increase the risk of insomnia, anxiety, depression, eating disorders, obsessive-compulsive tendencies, addiction, and PTSD. It could also have less predictable effects on bipolar disorder, schizophrenia, and ADHD.
Sulfite also inhibits the enzyme glutamate dehydrogenase, promoting an accumulation of glutamate, an excitatory NMDA receptor stimulating neurotransmitter that becomes excitotoxic in excess.
Sulfite also inhibits malate dehydrogenase, an enzyme important to energy production in the Krebs / Citric Acid Cycle. The Krebs / Citric Acid Cycle is the main source of citrate, the primary building block of myelin, the insulating sheath that enables nerves to conduct electrical impulses. So impairment of the Kreb's / Citric Acid Cycle in the brain could lead to demyelination that contributes to neurological issues that could disturb sleep.
Excess sulfite can further disrupt mitochondrial function by opening the mitochondrial permeability transition pore, allowing substances into the mitochondria that should not be there. Impairment of energy production in the brain limits the brain's ability to manage the highly energy-intensive process of regulating neurotransmitters. Lower energy production also reduces the synthesis of myelin.
Sulfite depletes the electron donor NADPH by activating the enzyme NADPH oxidase that uses NADPH to produce superoxide to fight pathogens. NADPH is required to recycle tetrahydrobiopterin (BH4), a cofactor in the enzymes that convert amino acids into neurotransmitters.
When BH4 gets depleted (for example due to NADPH depletion), this leads to altered neurotransmitter metabolism because the synthesis of many key neurotransmitters depends on BH4. And this can cause problems for sleep.
For example, one of the enzymes that requires BH4 as a cofactor is phenylalanine hydroxylase, the enzyme that converts the amino acid phenylalanine to tyrosine, which is necessary for the production of dopamine, norepinephrine, and epinephrine. Accumulation of phenylalanine competes with the amino acid tryptophan for entry into the brain and also inhibits the enzyme that converts tryptophan into serotonin, the precursor for melatonin.
Another enzyme that requires BH4 as a cofactor is tryptophan hydroxylase, the enzyme that initiates the process of converting tryptophan into serotonin, which is required to produce melatonin. As you probably know, melatonin is often thought of as the "sleep hormone" because it is an important instigator of sleep, though it has many more functions than promoting sleep.
Usually, the net effect of sulfite-induced neurotransmitter dysregulation tends toward excitatory states like anxiety, mania, OCD, insomnia, chronic pain, hypersensation, and muscle spasticity or tension. The effects of elevated sulfite on sleep are likely due to increases in the excitatory neurotransmitter S-sulfocysteine, accumulation of glutamate via inhibition of glutamate dehydrogenase, and reduced synthesis of serotonin and melatonin via inhibition of hydroxylase enzymes.
The effects of impaired sulfite clearance on neurotransmitters also increase the risk of seizures, tremors, tics, jerks, Parkinsonian movement disorders, gait disorders, and other neurological disorders.
How Sulfite Promotes Mast Cell Activation Syndrome (MCAS) and Allergy Symptoms
Mast Cell Activation Syndrome (MCAS) is another disorder with an excitatory neurological component. And via a sequence of effects on cell membrane stability, sulfite promotes degranulation of mast cells and the release of compounds like histamine. The combination of the excitatory neurological effects of sulfite and its promotion of mast cell degranulation suggests that elevated sulfite would tend to promote MCAS via mast cell sensitization. Excess sulfite can also increase mast cell death.
Sulfite's effect on histamine release can also increase allergy symptoms. It is possible that a mild allergy that would not produce symptoms in most situations could produce symptoms in those situations when sulfite is elevated.
Sources of Excess Sulfite
As described in the previous article, Could Testosterone and Estrogen Issues Be Related to Imbalanced Sulfur Metabolism?, sulfite accumulates when the enzyme sulfite oxidase does not function efficiently, which can be due to molybdenum deficiency or a genetic variant in the gene for sulfite oxidase (SUOX) or in genes for the molybdenum cofactor, which enables molybdenum to act as a cofactor for enzymes like SUOX.
Sulfite can also accumulate due to excess hydrogen sulfide. Elevated hydrogen sulfide leads to elevated sulfite via several steps. First, hydrogen sulfide releases free iron and impairs Complex IV in the mitochondria's electron transport chain (ETC), which lead to lower glutathione levels. When glutathione is low, the body upregulates its production of cysteine from homocysteine for use in glutathione synthesis. Increased production of cysteine increases sulfite because sulfite is a byproduct when cysteine gets oxidized (broken down) for energy, such as during fasting or carbohydrate restriction. In other words, When the body needs to produce glucose from amino acids and converts cysteine to glucose, sulfite is a byproduct.
Other sources of oxidative stress, not just excess hydrogen sulfide, also tend to lower glutathione and increase cysteine production, thereby raising sulfite as a byproduct of increased cysteine production and oxidation.
However, the production of sulfite from cysteine only poses a problem if molybdenum is deficient or if there are genetic variants in the SUOX gene or in genes involved in producing the molybdenum cofactor that enables molybdenum to act as a cofactor for enzymes like SUOX.
Do You Get "Hangry" or "Low Blood Sugar"?
Do you get irritable when you're hungry ("hangry")?
When the body uses cysteine to produce glucose, releasing sulfite in the process, the result can be irritability, anxiety, and ease of being startled, symptoms likely due to the effect of sulfite on neurotransmitters (e.g. an increase in S-sulfocysteine and its stimulation of NMDA receptors).
People often think of these symptoms as being symptoms of having "low blood sugar". But many of the symptoms that you might think of as symptoms of "low blood sugar" when you're hungry may not be the result of low blood sugar but rather may be neurological symptoms caused by S-sulfocysteine acting on NMDA receptors as your body converts cysteine to glucose, releasing sulfite in the process, which then combines with cysteine to produce S-sulfocysteine.
Sources of Excess Hydrogen Sulfide
Since elevated sulfite can result from elevated hydrogen sulfide, we need to look at what can cause elevations in hydrogen sulfide.
As described in the previous article, Could Testosterone and Estrogen Issues Be Related to Imbalanced Sulfur Metabolism?, hydrogen sulfide can be produced by certain gut bacteria, which could lead to elevated hydrogen sulfide in the body if there are problems with the function of the enzymes sulfide quinone reductase (SQOR gene), thiosulfate sulfurtransferase (TST gene), and/or persulfide dioxygenase (ETHE1 gene) that coordinate to break down hydrogen sulfide to sulfite, which can then be converted to sulfate by sulfite oxidase (SUOX gene).
This could occur due to genetic variants in the SQOR gene or deficiencies in its cofactors (FAD/riboflavin and coenzyme Q10), genetic variants in the TST gene or a deficiency in its cofactor (vitamin B6 in its pyridoxal-5-phosphate form), or genetic variants in the ETHE1 gene or deficiencies in its cofactors (iron and possibly glutathione), or conditions generally affecting the production of enzymes in the gut, such as inflammation and/or B1 deficiency.
Hydrogen Sulfide, Your Gut, Nutritional Status, and Energy
In the gut, excess hydrogen sulfide promotes diarrhea, loose stools, or excessive intestinal motility. This can promote nutrient deficiencies with broad effects throughout the body.
And because of hydrogen sulfide's impacts on mitochondrial energy production (displaces oxygen at Complex IV in the electron transport chain), elevated hydrogen sulfide in the body could contribute to fatigue.
How to Know if Impaired Sulfur Metabolism is Affecting You
Determining whether elevated sulfite and/or hydrogen sulfide are causes of your symptoms requires a combination of lab testing and symptom analysis. Tests that can help include organic acids, micronutrients, methylation metabolites, lactic acid, pyruvic acid, and hydrogen sulfide in breath.
If you would like any help with this, you can learn more about my overall approach by downloading the Bio-Individual Blueprint Roadmap and watching the walkthrough video. If you have already done that and are interested in speaking about potentially working together, you can schedule a time here.