Sulfation or Sulfate Conjugation
What Is Sulfation?
Sulfation is a conjugation process and it is involved in various body processes from the biotransformation/detox pathways to biosynthesis of some proteins. Sulfation is involved in a variety of biological processes, including detoxification, hormone regulation, molecular recognition, cell signaling, and viral entry into cells. Sulfation of xenobiotics is associated with biotransformation of a relatively hydrophobic or non water-soluble xenobiotic into a highly water-soluble sulfuric ester that is readily excreted in the urine. Sulfation has been shown to be an important pathway in the biotransformation of numerous xenobiotics (foreign or exogensous substances) such as drugs, and endogenous (made in your body) compounds such as hormones, bile acids, neurotransmitters, peptides, and lipids. Additionally sulfation is important in the biosynthesis of proteins, petptides, gycosaminoglycans (GAGs) and intestinal mucins.
Sulfation of hormones allow transport of hormones in the blood to target tissues. Sulfation can also be used for stabilization, and storage for some bio-signaling molecules. The sulfated hormones can be de-sulfated, or re-activated at target tissues when they are needed. It is known that sulfotransferase enzymes also catalyze this reverse reaction. It is thought by some researchers that plant polyphenols may also become sulfated, or go through glucuronidation (another conjugation process) and be carried through the body to end point locations, where they too are then de-sulfated, or de-glucuronidated, and are able to act at a point of inflammation, and oxidation. Here they can be released to act as antioxidants, and anti-inflammatories. (Well, I added some personal opinions there, but basically this is what researchers are theorizing from study results.) This has not been proven, but does look highly probable. I go into this further in my book Herbal ABCs - The Foundation Of Herbal Medicine. You will find these details in the "Endocrine - Reproductive Section" in the subsection on "Phytoestrogen Metabolism" where I use the example of metabolism of flavonoids (a type of polyphenol).
Sulfation And The Biotransformation/Detox Process
Sulfation is used to conjugate toxins with sulfur-containing compounds. This process is catalyzed by the super-family of sulfotranferases (SULTs). The sulfation system is important for detoxifying industrial, and environmental chemicals, several drugs, steroids, food additives, and toxins from intestinal bacteria. In addition, sulfation is also used to detoxify some normal body chemicals, and is the main pathway for the elimination of catecholamine neurotransmitters, steroid hormones, thyroid hormones, and glucocorticoid hormones, as well as conjugate bile acids. Since sulfation is also the primary route for the elimination of neurotransmitters, dysfunction in this system may contribute to the development of some nervous system disorders. Sulfation is one of the major detoxifying enzymes for phenolic xenobiotics. In most cases, the addition of active sulfate moiety (small particle) to a compound increases its water solubility, and decreases its biological activity. However, many of these enzymes are also capable of bioactivating procarcinogens to reactive electrophiles that are both mutagenic and carcinogenic.
A Major Conjugation Pathway For Some Chemicals
Sulfation is a major conjugation pathway for phenol, but can also occur for alcohols, arylamines, N-hydroxy compounds and to a lesser extent, thiols.
Sulfation Requires Enzymes And Co-substrates
The sulfation reaction needs a sulfotransferase (SULT) enzyme as a catalyst and a co-substrate as a sulfuryl donor. The universal donor for these reactions is what is known as "active sulfate" or 3′-phosphoadenosine 5′-phosphosulfate (PAPS). Sulfation has an entire enzyme family called sulfotransferases that are available as enzyme catalysts. All these sulfotransferases, use activated sulfate (PAPS [3′-phosphoadenyl-5′-phosphosulfate]) as a high-energy donor.
The Body Makes PAPS On Demand
PAPS is made from sulfate. Making PAPS from sulfate is dependent on availability of adensoine-5-triphosphate (ATP). Magnesium is also necessary. PAPS is considered the universal donor for all sulfation pathways. PAPS can be used up completely in a 2 minute time period. Therefore, the body needs to rapidly make PAPS when Sulfate conjugation is required.
Sulfotransferases (SULTS) are a family of enzymes that transfer the sulfate group from PAPS onto the target substrate. High levels of sulfortransferases are found in the liver, there is also quite a bit in the intestine, the brain, and is found throughout the body.
Sulfotransferases represent a family of enzymes with a monomer molecular weight of≈34 kDa, located in the cytoplasmic fraction of various tissues. They catalyze the transfer of sulfate from 3′-phosphoadenosine-5′-phosphosulfate (PAPS) to usually a hydroxyl group of the substrate .
Different phenol sulfotransferases have been identified with significant activity towards iodothyronines. These include human SULT1A1, 1A2, 1A3, 1B1 and 1C2. These studies have indicated a large substrate preference of the recombinant enzymes as well as the native enzymes in human liver and kidney for 3,3’T2, the sulfation of which is catalyzed orders of magnitude faster than that of T3 or rT3, while sulfation of T4 is hardly detectable .
Surprisingly, it has also been demonstrated that human estrogen sulfo¬transferase (SULT1E1) is an important isoenzyme for sulfation of thyroid hormone. Although human SULT1E1 shows much higher affinities for estrogens (Km ≈μM) than for iodothyronines (Km μM), it is about as efficient as other isoenzymes in sulfating 3,3’T2 and T3, and much more efficient in sulfating rT3 and T4. Human tissues known to express SULT1E1 include liver, uterus, and mammary gland. In particular the enzyme expressed in the endometrium may be a significant source for the high levels of iodothyronine sulfates in human fetal plasma.
Sulfation is a primary step leading to the irreversible degradation of T4 and T3 by D1 (one type of enzyme catalyzing deiodination). However, if D1 activity is low, inactivation of thyroid hormone by sulfation is reversible due to expression of sulfatases in different tissues and by intestinal bacteria. It has been speculated that especially in the fetus T3S has an important function as a reservoir from which active T3 may be released in a tissue-specific and time-dependent manner.
Human phenol sulfotransferase (SULT1A1) is one of the major detoxifying enzymes for phenolic xenobiotics. It is widely distributed in human tissues. It has very broad substrate specificity, and high catalytic activity toward most phenolic compounds. It not only sulfates simple xenobiotic phenols with high activity, but also sulfates many endogenous phenolic molecules, including hormones and neurotransmitters. Sulfation of xenobiotic phenols will lead to metabolism and detoxification of the toxicants. Sulfation of endogenous bio-signaling molecules by SULT regulates their biological activity. Sulfation of hormones also increases their solubility, and increases the transport of hormones in the blood to target tissues. Sulfation can also be used for stabilization, and storage for some bio-signaling molecules.
The sulfated hormones can be de-sulfated or re-activated at target tissues when they are needed. It is known that SULTs also catalyze the reverse reaction.
Sult1-A1: Sult1-A1 is selective for phenol substrates and can be found in high amounts in the liver, intestine, brain and platelets, although it is found throughout the body. Examples of substrates include paracetamol, minoxidil, troglitazone, apomorphine, 4-OH tamoxifen, iodothyronines.
SULT1A2: SULT1A2 is found in the liver - substrates not known currently.
SULT1-A3: Sulta-A3 is selective for catecholammines as well as phenol substrates and is mainly found in the intestine - Examples of substrates include dopamine, norepinephrine, carbidopa, L-Dopa, salbutamol, dobutamine
SULT-1E1: Ethinylestradiol(4-oh Tamoxifen), Raloxifene, diethylstilbestrol, estradiol, estrone, iodothyronines are all substrates.
Sulfate from PAPS is need as a substrate for sulfate conjugation. Paps is supplying the sulfate. Low levels of PAPS exist in the body but are synthesized quickly as needed from inorganic sulfate, or catabolism of cysteine and methionine.
Co-substrate depletion: Reduced inorganic sulfate, cysteine and methionine can cause a co-substrate-dependent decrease in sulfation rates. An example of when this is seen is in association with high doses of acetaminophen.
Substrates Of Sulfation In The Body
Endogenous substrates for sulfation are steroids, bile acids, phenols, neurotransmitters, proteins and carbohydrates.
Glucuronidation And Sulfation Share Substrates
Frequently phenols have both glucuronidation, and sulfation as competing conjugation reactions.
Sulfation is often a high affinity, low capacity pathway, while glucuronidation is frequently a low affinity, high capacity. Thus, at a low dose sulfation may dominate, but as the dose of the substrate/phenol increases , glucuronidation can become the major route.
The Fate of A Substance Conjugated With Sulfate
Sulfation is subject to reversible metabolism, meaning as with many conjugation processes, it can be unconjugated.
Sulfate conjugates are frequently excreted in urine, although some bile acid sulfates are excreted into the bile.
Sulfate metabolites are usually inactive and therefore safe, but not always. Sulfates are strong acids pKa <1. As an acid, sulfates often bind to albumin. Sulfate metabolites are usually excreted by the kidney, though for larger molecules, sulfates can be excreted in the bile.
Sulfation Biotransforms Two Main Classes Of Compounds, Phenols And Amines
Sulfation of these two groups of compounds is necessary for our bodies to remove them so they don't build up.
Phenols are a group of chemical compounds consisting of a hydroxyl group (-OH) bonded directly to an aromatic ring. They are called “aromatic” because many of the compounds have a sweet scent. Phenols can be synthesized as a variety of chemicals, as well as occurring naturally in nature. Phenols are easily absorbed by inhalation, skin contact and ingestion.
Sources Of Human Made Phenols
- Bisphenol A, B
- Various herbicides
- Various pesticides
- Various fungicides
- The well known hand cleaner Triclosan
Sources Of Natural Phenols
- Cresols found in foods, and crude oil, and coal tar
- Capsaicinoids from Capsicum spp.,
- Eugenol found in Clove, Nutmeg, Cinnamin, Bay and Basil.
- Flavonoids are polyphenols, and one of the largest group of natural phenols found in plants.
- Salicylic acid, salicylates are types of phenol found in food and herbs.
Phenol Compounds Made By The Body
- Steroid hormones
- sex steroids,
- bile acids
- iodothyronines (T3,T4).
Amines are a group of chemical compounds that contain nitrogen. Amines are derived from ammonia. One or more hydrogens are replaced with another atom. They are strong smelling, and often thought to smell "fishy". Amines are constituents of amino acids, they are found in vitamins and many drugs.
Amines Found In The Body
- Neurotransmitters called phenol amines
- Amino acids
- aspartic acid
- glutamic acid
- Amines Found In Aged Foods
Many aged cheeses contain tyramine from tyrosine breaking down into tyramine. Amines are also found in the thousands of plant alkaloids in nature. Examples of these alkaloids are morphine, ephedrine, nicotine, berberine.
- Exogenous amines
Exogenous amines are found in aniline which is an aromatic amine used to make acetaminophen, and blue dye. Ethanolamines are found in antifeeze, and used as emulsifiers in many household products such as ice cream.
Sulfation Used To Make Necessary Substances
Besides transformation of toxins sulfation is used by the body to create new and useful compounds. Examples are synthesis of sulfonated gycosaminoglycans, such as chrondroitin sulfate ( in ligaments, cartilage and tendons), dermatan sulfate (Found in vasculature, the cardiac valves and skin), heparan sulfate (attached to almost all cell surfaces and found in the basement membrane of epithelial tissues), keratin sulfate (Found in loose connective tissues in connection with chondroitin) and heaparin (a part of mast cells, found in the skin, lungs and liver). Sulfation is also used by the body to synthesize mucins, cholecystokinin, and gastrin.
Sulfation Used To Activate Necessary Substances
Sulfation Of Cholecystokinin Necessary For Activity
Cholecystokinin (a neuroendocrine hormone and necessary for digestion) is a linear peptide that is synthesized as a preprohormone, then proteolytically cleaved to generate a family of peptides having the same carboxy ends. Full biologic activity is retained in CCK-8 (8 amino acids), but peptides of 33, 38 and 59 amino acids are also produced. In all of these CCK peptides, the tyrosine seven residues from the end is sulfated, which is necessary for activity.
Researchers claim about one-third of T4 is converted to T3 and about one-third to rT3. The remainder of T4 is metabolized by different pathways, in particular glucuronidation and sulfation.
Further, for some drugs such as the hair growth stimulant, minoxidil and the neuroendocrine peptide cholecystokinin, they need to be sulfonated to have a biological effect.
Sulfite Food And Drug Additives
Sulfation is the second part of the process by which the body eliminates the sulfite food additives used to preserve many foods and drugs.
Sulfation And Sulfate Oxidase Activity Are Different Processes
Various sulfites are widely used in potato salad (as a preservative), salad bars (to keep the vegetables looking fresh), dried fruits (sulfites keep dried apricots orange), and some drugs. Normally, the enzyme sulfite oxidase metabolizes sulfites to the safer, and needed sulfates which is a process called sulfoxidation. Those with a poorly functioning sulfoxidation system, however, have an increased ratio of sulfite to sulfate in their urine.
To convert sulfites to sulfate in the process of sulfoxidation (SUOX) the co-factor molybdenum is needed for enzymatic action. Glyphosate is a known chelator of molybdenum and could be a cause of sulfite oxidase dysfunction. Additionally, B-12, B-2, manganese, boron and strontium are needed to make sulfate. People with issues in the sulfoxidation process tend to get headaches/migraines, asthma or chest tightness, chronic fatigue, and chronic indigestion and heartburn. They may react to high sulfur foods such as the Cruciferae or mustard family vegetables or other high sulfur plants such as Garlic, and Eggs. The sulfate in Epsom salts could cause a reaction if the makeup of the colonic bacteria includes more of them that change sulfate back into sulfur such as Escherichia coli. In this case the sulfate is changed to hydrogen sulfide and further into sulfur amino acids. This could down the line, eventually add to an increase in sulfite to sulfate ratio if there is low sulfate oxidase. Keep in mind if the individual has high oxalate levels this also could cause a reaction when Epsom salts or other sources of sulfur increase sulfate in the body as sulfate is used to help remove oxalates from the body and if increased quickly can cause a sudden movement of oxalates that becomes a painful experience. This would only be noticed in someone who has low sulfate and suddenly increases it.
Deconjugation is possible sulfates can hydrolyze within physicological ph range.
Genetics And SULTS
The cytosolic SULTs are derived from a large superfamily of genes. The SULT1 and SULT2 families are the largest, and probably the most important for xenobiotic and endobiotic metabolism. Activity of these enzymes vary widely in the human population.
SULT Family 1
SULT1A1 is important for xenobiotic detoxification, thyroid hormone metabolism and the bioactivation of procarcinogens. It is subject to a common functional polymorphism.
It is also interesting that a significant age-related effect on SULT1A1 genotype has been observed, whereby the frequency of the SULT1A1*1 allele was higher in the older age-groups. This observation raises the possibility that the genotype responsible for a high sulfation activity phenotype may provide some protection against long-term cell/tissue damage from xenobiotic and/or endogenous chemicals, and as such would support a major role for SULT1A1 in detoxification.
SULT1A1*1 homozygosity is associated with reduced risk of colorectal cancer
However, a large study of breast cancer patients showed no overall effect of SULT1A1 genotype on risk of developing the disease, although these authors did demonstrate that genotype may be associated with age of onset of breast cancer. In contrast, investigation of another breast cancer patient cohort showed increased risk associated with SULT1A1*1 genotype when combined with intake of well-done meat, a significant source of many heterocyclic amines that are bioactivated by human SULTs including SULT1A1. To further complicate matters, this same study found that overall risk of breast cancer was associated with the SULT1A1*2 allele. A small study of prostate cancer failed to find any association with SULT1A1 genotype.
Sequencing of the human SULT1C2 gene from different individuals has revealed four SNPs, and recombinant allozymes representing three of these displayed, reduced enzyme activity compared to the wild-type allozyme. The consequences for the individual of possessing these variant alleles and/or expressing the transcript variant are unknown, although the SULT1C2 enzyme is expressed at high levels in fetal tissues and has been implicated in the bioactivation of aromatic amines, and also in the metabolism of iodothyronines. A single SNP in SULT1C4 (Asp5Glu) was identified in a sequencing study of many SULT genes in 48 Japanese individuals, although no allele frequency or allozyme function data were reported.
The expression and activity of SULT1E1 varies widely in the human population, although it is not known whether this is under genetic control. No evidence for gender-specific regulation in liver was found, although the enzyme is expressed in female-specific tissues, including the endometrium. It is possible that the variability in SULT1E1 expression results from different chemical influences, since progesterone, other hormones and alcohol are known to influence expression levels in vitro and/or in vivo. Not much data on SULT1E1 at the time of writing this.
SULT Families 2 and 4
Circulating DHEA sulfate levels vary substantially between individuals, and it is suggested that this variation is, at least in part, inherited. It is hypothesised that inter-individual variation in the expression and/or activity of SULT2A1 might therefore contribute to these differences in DHEA sulfate levels. DHEA SULT activity in human liver cytosols appears to follow a bimodal distribution, and a strong correlation between enzyme activity and protein expression exists. However, extensive gene sequencing studies failed to identify the variant alleles represented by cDNAs. The authors did report two cSNPs (Met57Thr, Glu186Val) with allele frequencies around 3% which have been assigned the preliminary designation *2 and *3, respectively. The SULT2A1*2 and *3 allozymes showed decreased enzyme activity when expressed in COS cells. Three cSNPs in SULT2A1 (Ala63Pro, Lys227Glu and Ala261Thr) were also reported by the Pharmacogenetics Knowledge Base.
Factors Influencing The Activity Of Sulfate Conjugation
Inhibition Of Sulfation
Many factors influence the activity of sulfate conjugation. For example, a diet low in methionine and cysteine has been shown to reduce sulfation. This is because they can be used as building blocks to make sulfate.
When there is more than one compound that is transformed by a single enzyme, there is what is called competative inhibition. In this case one compound is unable to be transformed due to the competition of the other compound. The compound being transformed will bind the active site of the enzyme and the other compound simply can't use it now. If aperson is around a lot of essential oils that have phenols and eating a lot of high phenol foods they may end up without enough sulfates for sulfation. They might run out of enzymes. If the person has a high oxalate problem, they will surely be running out of sulfates if the hyperoxaluria (exogenous or endogenous caused) is not being treated and they will definitely be reacting to foods with oxalates and phenols in them as well as any essential oils or chemicals containing phenols that are floating through the air.
An increase in toxins from the environment or bacteria in the gut can also lead to what is called inhibition due to increased toxic load. I would not really call this inhibition, although researchers do, but it does decrease enzymes available. It is simply a case of using up available enzymes faster than they can be made. Bacteria and fungus such as the Candida yeast can cause decreaesed availabilty of sulfation enzymes.
One mechanism of inhibition is depletion of necessary cofactors. Sulfation is particulary susceptible to inhibition due to depletion of cofactors. There is a delicate balance of serum sulfate concentration. This relies on the absorption of inorganic sulfate, and it production from cysteine on one hand, and the elimination of sulfate by urinary excretion, and sulfation of low molecular weight substrates on the other hand.
Over a 24 hour period the serum sulfate levels in a person vary dramatically. It will decrease if fasting, or eating a lot of substances that are metabolized by sulfation (acetaminophen). A person excretes about 20-25 millimoles of sulfate in a 24 hour period. Sulfate reserves must be continuously maintained by dietary intake of sulfur-containing amino acids or inorganic sulfate. Both will increase serum sulfate levels.
When sulfation is inhibited a person is unable to detoxify, and elminate tylenol as well as adrenaline and dopamine from the brain.
Inhibitors Of Sulfation
- Non-steroidal anti-inflammatory drugs (e.g. aspirin)
- Tartrazine (yellow food dye)
Anything that will enhance production of cysteine (building block to make sulfate) will help induce sulfation. N-acetyl cysteine (NAC) is a supplement that can be used as a substrate to ultimately make sulfate. It involves multiple steps needing multiple enzymes as well as iron, tyrosine, B6, B2 and molybdenum. I have included a diagram below, that shows the oxidative, and non-oxidative pathways for cysteine to become sulfate. Be careful about taking any product such as NAC that is a chelator as they can chelate out toxins such as mercury or mycotoxins and if you take too high a dose or do is sporadically, it may cause symptoms from pulling out the toxins in an unconscious and haphazard manner.
Not shown on this chart is the production of hydrogen sulfide (toxic in excess, necessary in small amounts) when homocysteine is changed into cystathionine and again when cystathionine is changed into cysteine. The signaling molecule, hydrogen sulfide travels through bodily tissue by simple diffusion, so it easily moves around. Usually involved in blood vessel relaxation, neuromodulation, angiogenesis, regulation of inflammatory response, insulin release, energy metabolism and cardioprotection; it can also contains inorganic sulfur and can be oxidized as a source for sulfate. The process of clearing excess hydrogen sulfide both is protective to the body while supplying the much needed sulfate. The mitochondrial sulfide oxidation pathway couples sulfide catabolism to oxidative phosphorylation, making sulfide an inorganic substrate for the human electron transfer chain.
As you can see below sulfite oxidase (encoded by the nuclear SUOX gene) catalyzes the final step of cysteine catabolism thereby oxidizing sulfite to sulfate.
Sources Of Sulfur To Make Sulfate
Food As A Source
Cruciferous vegetables such as broccoli, kale, cauliflower, cabbage, brussel sprouts, bok choy turnip, radish, kohlrabi and mustard are a source of sulfur as are the Alliums such as garlic, scallions, leeks chives, shallots and onions. These plants contain sulfur containing constituents such as glucosinolates, sulforaphane, isothiocyanates.
Amino acids found in proteins such as methionine and cysteine. Sufur rich animal foods include beef, chicken, lamb, turkey, duck, pork, milk, cheese and eggs.
The majority of sulfur is obtained from amino acids.
Sulfur containing molecules found in the body include:
- B vitamins biotin, Pantothenine (B5) and Thiamin (B1)
- S-adenosylmethionine (SAMe)
- Alpha lipoic acid (AKA thioctic acid)
Nutritional Supplements Containing Sulfur
Supplements that contain sulfur include:
- Alpha lipoic acid
- Chondroitin sulfate
- Glucosamine sulfate
- Indole-3 -carbinol
- N-acetyl cysteine
Using Supplements And Food To Supply Sulfur
For people with oxalate issues, they need to add sulfur or sulfate in the forms of supplements or baths slowly, as it will help remove the oxalates and can bring on a painful crisis as the oxalates are moved around. These people need to start slowly.
The issue with useing amino acids, or supplements such as NAC, that supply sulfur compounds, is that the body needs to change the sulfur first into sulfite through a reaction such as sulfoxidation and then using sulfite oxidase, change the sulfite into sulfate. This step needs molybdenum, B-12, B-2, manganese, boron and strontium for it to take place. Another way to supply sulfate is through Epsom salt baths which contain magensium sulfate.
- NAC - remember this is a chelator and needs to be used cautiously if someone has toxins that may be chelated out of cells and therefore cause symptoms.
- Resveratrol is a substrate for sulfation as well as glucuronidation. Reseveratrol induces UGT1A1 transcription.
Substrates that may be used for sulfation and sulfoxidation: Sulfur containing foods in general, NAC, methionine molybdenum, B2 and B6, vitamin A, and adequate protein. Epsom salts are a great way to get ready made sulfate into the body buy soaking in an Epsom salt bath. This bypasses the need to make sulfate if someone is low in sulfate.
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