SULT1a1 - Sulfur Issues Again

This article is not intended to be healthcare or medical advice. Before starting any health related regimen seek the advice of your Primary Care Physician or an M.D.

This gene processes a number of important compounds, and is critical in the sulfation, and heme pathways. Recent research findings indicate this gene can be blocked/inhibited by a number of common foods, compounds, environmental exposures, and even a B vitamin! This gene could be limited in its capacity from genetic mutations and or the inhibiting agents noted below. In either case, i have seen several cases recently where this has been a big issues, and once resolved, many things improved. We dont want to inhibit this gene on an ongoing basis. This doesn't mean you can never have anything on the lists below, but rather, not always. Pulsing, 3 days on 3 days of, etc could be one strategy, along with general reduction in the inhibitors overall.

Some of the more common lab markers that can become dysregulated when this gene is compromised are : dysregulation in the heme cycle - low hemoglobin, porphyrin dysregulation, low blood oxygen, low glutathione, and high reactivity to phenol, and oxalate compounds. There even appears to be a link to ADHD and SULT1a1 activity based on the work of one of the more well known researchers on SULT1a1, Ken Eagle.[11,12]

Why Is SULT1A Important ?

SULT1A1 performs sulfate conjugation of catecholamines, phenolic drugs, neurotransmitters, serotonin, plant based phenols, e.g. flavonoids, tannins, stilbenes and others. Also has estrogen sulfotransferase activity.  Sulfur, phenols, and oxalates all go through this pathway. steroids, Eicosanoids, Serotonin, Dopamine, Catecholamines, Iodothyronines, 6-hydroxymelatonin, Retinol, Vitamin D, Bile Acids, Peptides, and Lipids. This is alot, and many anti oxidant and anti inflammatory compounds fall into these categories - see the lists below for the inhibitors.

An alternative pathway to process serotonin, when SULT1a1 is compromised is through UGT1A6, part of the glucuronidation system of enzymes.

List of SULT1A1 inhibitors:

Foods and compounds that can inhibit SULT1a1: See detailed list below.

B6 (PLP a form of b6 that the body creates, blocks Sult1a1)

Chlorinated water

N'SAID's [6]

Oxidized glutathione [7]

Phthalates [5]

Diacetyl, Butanedione [8] - see additional food lists below

Circumin

Phenols

Salicylate Acid

Citrus juices like grape and orange

Flavanoids in fruits and vegetables

NSAID's

List of compounds that active SULT1A1

Sulfate - think epson salt baths

Arginine (see arg1 blog article), and nuts [8]

glucocorticoid triamcinolone acetonide [9, 10]

Caffeine (coffee, green tea, black tea, cocoa, matcha)

Retinoic Acid (Vit A - not beta carotene, cod liver oil)

Dill (the herb)

List of Compounds With Sulfur that can induce sulfation

• Legumes, grains, beans, peas, oatmeal, barley

• Nuts, seeds

• Ginger

List of Compounds that significantly inhibit Sult1a1 [1]:

Quercetin, Circumin, Nubiletin, Tangeretin, Catechin, Epicatechin gallate, Epigallocatachen gallate, Gallocatechin gallate, theaflavins from fractions black tea, therabugin from fractions of black tea, Eriodictyol, Carmoisine, Lyanidin 3-Rutinoside, Salicylic Acid

List of Foods that Contain the above Compounds [1,2]:

Chocolate, Onion, Blueberry, lime, orange, lemon, tumeric, lingonberry, muscaldine wine, brandy, red wine, wiskey, white wine, cacao, tea, peacans, synthetic colorante E122, Black currant, cherries, olives, fennel, cranberry, cinnamon,  cheese, juices (apple, grape, grapefruit), teas (green and black) and coffee.

Common Foods Containing Diacetyl - due to butter flavoring additions [14-20]

Popcorn, Potato chips, Crackers, Corn chips

It is used as a flavoring agent in butter, butter sprays, margarine, shortening, oil, oil sprays and other butter-flavored substances.

Diacetyl is also used as a brown flavor sweetening additive in products such as [14-20]:

Chocolate, Cookies, Cocoa-flavor products, Gelatin, Candy, Flour mixes, Syrup with flavoring,

Frostings, Chewing gum, Ice cream, Soft drinks, Sauces

Along with processed foods, diacetyl occurs naturally in some foods and beverages [14-20]:

Dairy products such as milk, cheese, yogurt and butter

Beer and wine – found in the fermentation of alcohol

Honey and most fruits

Coffee, coffee beans, coffee grounds

Sult1a1 In Holiday Heart / Cardiac Events

"SULT1A enzymes protect humans from catecholamines, but natural substances in many foods have been found to inhibit these enzymes in vitro. Given the hormonal roles of catecholamines, any in vivo SULT1A inhibition could have serious consequences. This paper uses a re-analysis of published data to confirm that SULT1A inhibitors have effect in vivo in at least some patients. Nineteen studies are cited that show ingestion of SULT1A inhibitors leading to catecholamine increases, blood pressure changes, migraine headaches, or atrial fibrillation. SULT1A inhibition does not create the catecholamines, but prevents normal catecholamine deactivation. Susceptible patients probably have lower-activity SULT1A alleles. The paper discusses new hypotheses that SULT1A inhibition can cause “holiday heart” arrhythmias and type 2 diabetes in susceptible patients. Subgroup analysis based on SULT1A alleles, and addition of a catecholamine source, should improve the consistency of results from tests of SULT1A inhibitors. SULT1A inhibition may be a key contributor to cheese-induced migraines (via annatto), false positives in metanephrine testing, and the cardiovascular impacts of recreational alcohols. Dietary SULT1A inhibition causes migraines in susceptible people. SULT1A inhibition may cause “holiday heart” and diabetes in susceptible people. "[1]

Certain Xenobiotics Inhibit SULT1a1 - Aspirin, BPA, etc

"SULT activity may be inhibited when humans are exposed to certain xenobiotics including drugs (mefenamic acid, salicylic acid, clomiphene, danazol etc.), dietary chemicals (catechins, food colorants, flavonoids and phytoestrogens etc.), and environmental chemicals (hydroxylated polychlorinated biphenyls, hydroxylated polyhalogenated aromatic hydrocarbons, pentachlorophenol, triclosan and bisphenol A, etc.). Inhibition of individual SULT isoforms may cause adverse effects on human health. For example, hydroxylated polychlorinated biphenyls have been shown to interfere with the transport of thyroid hormones, inhibit estradiol sulfonation, and inhibit thyroid hormone sulfonation, thereby potentially disrupting the thyroid hormone system. Formation of sulfate conjugates of toxic xenobiotics usually decreases their toxicity, so inhibition of this pathway may lead to prolonged exposure to the compounds. Conversely, some sulfate conjugates are chemically reactive, inhibition of their formation may protect from toxicity."[3]

Phthalates Inhibit SULT1a1

"Phthalate esters (PAEs) are softening chemicals that are widely used in homes and industries as plasticizers. PAEs are commonly used and can easily cause harm to human body. Humans are exposed to PAEs mainly through respiratory inhalation, skin absorption, and dietary intake"[5]

"Multiple phthalate monoesters have been demonstrated to exert strong inhibition potential towards SULT1A1, SULT1B1, and SULT1E1, and no significant inhibition of phthalate monoesters towards SULT1A3 was found. The activity of SULT1A1 was strongly inhibited by mono-hexyl phthalate (MHP), mono-octyl phthalate (MOP), mono-benzyl phthalate (MBZP), and mono-ethylhexyl phthalate (MEHP). Monobutyl phthalate (MBP), MHP, MOP, mono-cyclohexyl phthalate (MCHP), and MEHP significantly inhibited the activity of SULT1B1. MHP, MOP, and MEHP significantly inhibited the activity of SULT1E1. MOP was chosen as the representative phthalate monoester to determine the inhibition kinetic parameters (Ki) towards SULT1B1 and SULT1E1. The inhibition kinetic parameters (Ki) were calculated to be 2.23 μM for MOP-SULT1B1 and 5.54 μM for MOP-SULT1E1. In silico docking method was utilized to understand the inhibition mechanism of SULT1B1 by phthalate monoesters."[5]

Inhibition of sult1at1 by NSAIDs [6]

"In summary, each of the nine agents inhibited both human sulfotransferase isoforms, SULT1A1 and SULT1E1. Meclofenamate, nimesulide, piroxicam, sulindac, ibuprofen, Salicylic Acid, Indomethacin, Aspirin, Naproxen.

Oxidized Glutathione / Redox Imbalance Can Inhibit SULT Enzymes

"Our results suggest that active site Cys residue modification caused the inactivation of hSULT1E1. The inactivation reaction order suggested that one Cys residue in the active site of hSULT1E1 is crucial for redox regulation of its enzyme activity. These results are in agreement with crystal structures of human SULTs. Crystal structures suggest that no Cys residues exist near the active sites of hSULT1A1, hSULT1A3, and hSULT2A1. For hSULT1E1, Cys83 and Cys128 are located near the active site. Our site-directed mutagenesis results demonstrated that the presence of Cys83 is crucial for the GSSG inactivation of hSULT1E1.

To the best of our knowledge, oxidative regulation of human SULTs has not been reported. Our results suggest a potential oxidative regulation mechanism for hSULT1E1 through Cys83 redox modification. Cys83 is located in the active site and is in direct contact (6Å) with the substrate E2. Moreover the –SH group of Cys83 is directed toward the E2 molecule based on its crystal structure. Cys83 modification by a bulky molecule like -SG was sufficient to inactivate hSULT1E1, probably by inhibiting substrate binding or product release. Mutant Cys83Ser remained enzymatically active, suggesting that Cys83 is not a critical residue for hSULT1E1 catalytic activity. Ser residue is structurally similar to Cys residue. The Cys/Ser mutation only results a replacement of the –SH group with the –OH group. The mutation should not cause other structural or chemical property changes of hSULT1E1 except the redox regulation property. When the –SH group is replaced with –OH group, although the catalytic activity of hSULT1E1 is not significantly changed, its redox regulation property is significantly changed. This strongly supports the hypothesis that Cys83 is responsible for the redox regulation of hSULT1E1. This also suggests the potential oxidative regulation mechanism for hSULT1E1."[7]

Butanedione , Diacetyl [8, 13-20]

Butanedione (BD) inactivated SULT1A1 in an efficient, time- and concentration-dependent manner. This further demonstrates that BD is a specific reagent for the inactivation of critical Arg residues in the active site of SULT1A1. The BD reaction order, n, is ~1. This suggests that there may be only one Arg residue in the active site whose modification could lead to complete inactivation of SULT1A1.[8]

Diacetyl (also called 2,3-butanedione) is a chemical that has been used to give butter-like and other flavors to food products, including popcorn. Diacetyl is most prevalent in processed foods that contain butter flavoring. It is used as a flavoring agent in butter, butter sprays, margarine, shortening, oil, oil sprays and other butter-flavored substances. If a product is advertised as having “buttery flavor,” then that product likely contains diacetyl.[14] Its also linked to various lung related illnesses and injury. [14-20]

SULT1a1, SULT3a1 in ADHD and Behavioral Health [11,12]

"Five recent reviews have analyzed trials on the association between artificial food colors and ADHD; the 50 underlying studies and the reviews in aggregate were inconclusive. Recent work has shown human in vivo SULT1A inhibition leading to incremental catecholamines, and an inverted-U relationship between brain catecholamines and proper functioning of the prefrontal cortex where ADHD behavior can arise."

"SULT1A inhibitors in foods, including natural substances and artificial food colors, have a role in ADHD that can both worsen or improve symptoms. Mechanistically, SULT1A enzymes normally deactivate catecholamines, especially dopamine formed in the intestines; SULT1A inhibition can influence brain catecholamines through the intermediary of plasma tyrosine levels, which are influenced by dopamine inhibition of intestinal tyrosine hydroxylase."[11]

"In the present study, we have shown that dopamine induces both SULT1A1 and 1A3 in human neuronal cell lines by a mechanism involving both dopamine D1 and NMDA receptors. Moreover, this induction appears to protect cells from dopamine-induced cytotoxicity. Studies with siRNA that selectively targeted SULT1A3 showed that this sulfotransferase was responsible for the decreased toxicity in both SK-N-MC and SH-SY5Y cells.

The increased expression of SULT1A1/3 following dopamine treatment appeared to require gene activation because there was an increase in mRNA for both genes. Moreover, down-regulation of the transcription factor GABP, which previously has been shown to regulate SULT1A1 expression (38), prevented induction. Nevertheless, these data do not prove increased transcription of the SULT1A1/3 genes by dopamine as mRNA stability and/or protein stability could account for the results reported here. Regardless, the activation of D1 receptor and phosphorylation of ERK1/2 were necessary.

However, the latter by itself was not sufficient to increase SULT1A1/3 because neither norepinephrine nor dibutyryl cAMP increased either sulfotransferase despite increasing phospho-p44/p42. These results suggested that at least two converging pathways were involved in SULT1A1/3 induction. Using a range of pharmacological agents, we showed that induction involves coupling of the D1 and NMDA receptors and activation of calcineurin. Calcineurin, in turn, signals through several target proteins including the transcription factor NFAT. In rat islet cells, insulin induction by glucose requires the formation of NFAT-Maf and NFAT-C/EBP complexes, with ERK1/2 phosphorylation modulating the partners of the calcineurin-dependent NFAT. This co-dependent signaling has also been reported in cardiomyocytes, embryonic stem cells, and myoblasts.[12]

SULT1A3 joins a very long list of drug-metabolizing enzymes that are induced by their own substrates. This induction is usually dose-dependent, rapid, and reversible. In this study, we observed an increase in SULT1A1/3 as early as 8 h after treatment, and this was sustained for at least 48 h. These sulfotransferases are the first phase I or phase II enzymes shown to be induced by a dopamine D1-NMDA receptor-coupled mechanism. However, further human studies are required to confirm induction in vivo. The lack of an animal model for SULT1A3 will make these studies more challenging.[12]

A unique feature of the SULT1A3 gene is its presence only in primates. Several researchers have speculated that evolutionary pressure resulting from greater catecholamine demand in humans may be responsible for its emergence. Because SULT1A3 resides in a chromosomal region of low copy repeats (16p11.2), there is a possibility that multiple copies of the gene are present in humans, and like the CYP2D6 gene, copy number varies among individuals. Consistent with this notion is the recent discovery of an identical gene (SULT1A4) located at 16p12.1. To date, the SULT1A4 gene has only been found in humans, and evolutionary analysis indicates that it arose due to post speciation duplication. Given the results from the present study that indicate sulfonation is important in dopamine toxicity, gene copy number may be a significant risk factor in catecholamine-induced neurodegenerative disease. High copy number may be protective whereas low copy number, gene deletion, or a loss in inducibility may result in an increased susceptibility. A comprehensive study in appropriate cohorts is required to address this possibility."[12]

William Davis writes about how various sulfur pathways are implicated in human behavior, and suspected in postpartum depression as well. [13]

Cresol, yes the metabolite from Clostridia goes through SULT1a1, so this is another load on this pathway[22]. Metals like aluminum, and mercury also use sulfation in phase 2 detox / conjugation. SULT1a1 will benefit from support if there is significant genetic compromise here when dealing with issues like these.

If you would like to review your genetics in detail, discuss potential strategies and options to investigate if this is an issue that applies to you, and what options may be available please contact me to schedule an appointment or schedule one on-line.

References:

1. Toxicological effects of red wine, orange juice, and other dietary SULT1A inhibitors via excess catecholamines. Ken Eagle. Food and Chemical Toxicology. Volume 50, Issue 6, June 2012, Pages 2243-2249. https://doi.org/10.1016/j.fct.2012.03.004

2. Effects of Food Natural Products on the Biotransformation of PCBs

Margaret O. James, James C. Sacco, and Laura R Faux. Environ Toxicol Pharmacol. Author manuscript; available in PMC 2009 Mar 1. Environ Toxicol Pharmacol. 2008 Mar; 25(2): 211–217.

doi: 10.1016/j.etap.2007.10.024. PMCID: PMC2346442. NIHMSID: NIHMS40361. PMID: 19255595

3. Inhibition of sulfotransferases by xenobiotics. Li-Quan Wang 1, Margaret O James. Curr Drug Metab. . 2006 Jan;7(1):83-104. doi: 10.2174/138920006774832596. PMID: 16454694. DOI: 10.2174/138920006774832596

4. Migraine susceptibility is modulated by food triggers and analgesic overuse via sulfotransferase inhibition. Doga Vuralli, Burak Arslan, et al. Published: 14 March 2022. The Journal of Headache and Pain volume 23, Article number: 36 (2022)

5. Inhibition of Human Sulfotransferases by Phthalate Monoesters. Hui Huang1† Bei-Di Lan2†. Front. Endocrinol., 22 April 2022. Sec. Gut Endocrinology. Volume 13 - 2022 | https://doi.org/10.3389/fendo.2022.868105.

6. Inhibition of human phenol and estrogen sulfotransferase by certain non-steroidal anti-inflammatory agents. Roberta S. King,* Anasuya A. Ghosh,1 and Jinfang Wu

. Curr Drug Metab. Author manuscript; available in PMC 2007 Dec 4. Curr Drug Metab. 2006 Oct; 7(7): 745–753. doi: 10.2174/138920006778520615. PMCID: PMC2105742. NIHMSID: NIHMS33405. PMID: 17073578

7. Redox Regulation of Human Estrogen Sulfotransferase (hSULT1E1)†

Smarajit Maiti,§ Jimei Zhang,‡ and Guangping Chen§* Biochem Pharmacol. Author manuscript; available in PMC 2007 Aug 21. Biochem Pharmacol. 2007 May 1; 73(9): 1474–1481.

Published online 2006 Dec 28. doi: 10.1016/j.bcp.2006.12.026. PMCID: PMC1950446

NIHMSID: NIHMS21426. PMID: 17266938

8. Arginine Residues in the Active Site of Human Phenol Sulfotransferase (SULT1A1).

Guangping Chen, Xinrong Chen, et al. ENZYME CATALYSIS AND REGULATION| VOLUME 278, ISSUE 38. DOI:https://doi.org/10.1074/jbc.M306045200

9. Duanmu Z, Dunbar J, Falany CN, et al.. Induction of rat hepatic aryl sulfotransferase (SULT1A1) gene expression by triamcinolone acetonide: impact on minoxidil-mediated hypotension. Toxicol Appl Pharmacol 2000; 164: 312-20. [PubMed] [Google Scholar]

10. Duanmu Z, Kocarek TA, Runge-Morris M. Transcriptional regulation of rat hepatic aryl sulfotransferase (SULT1A1) gene expression by glucocorticoids. Drug Metab Dispos 2001; 29: 1130-5. [PubMed] [Google Scholar]

11. ADHD impacted by sulfotransferase (SULT1A) inhibition from artificial food colors and plant-based foods. Ken Eagle. Physiology & Behavior. Volume 135, August 2014, Pages 174-179. https://doi.org/10.1016/j.physbeh.2014.06.005

12. Cytosolic Sulfotransferase 1A3 Is Induced by Dopamine and Protects Neuronal Cells from Dopamine Toxicity. ROLE OF D1 RECEPTOR-N-METHYL-d-ASPARTATE RECEPTOR COUPLING. Neelima P. Sidharthan, Rodney F. Minchin,1 and Neville J. ButcherJ Biol Chem. 2013 Nov 29; 288(48): 34364–34374. Published online 2013 Oct 17. doi: 10.1074/jbc.M113.493239

PMCID: PMC3843051. PMID: 24136195

13. SULFATION PATHWAYS The steroid sulfate axis and its relationship to maternal behaviour and mental health. William Davies. Journal of Molecular Endocrinology. https://doi.org/10.1530/JME-17-0219. Volume 61: Issue 2. Page Range: T199–T210. online Publication Date:

Aug 2018. 2018 Society for Endocrinology 2018

14. Osha.gov

15. Fixed Obstructive Lung Disease in Workers at a Microwave Popcorn Factory — Missouri, 2000–2002. Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report 51(16); 345-7 (April 26, 2002).

16. Hubbs A., et al. "Necrosis of Nasal and Airway Epithelium in Rats Inhaling Vapors of Artificial Butter Flavoring." Toxicology and Applied Pharmacology 185(2002): 128-135.

17. Hubbs AF, et al.. "Respiratory toxicologic pathology of inhaled diacetyl in Sprague-Dawley rats." Toxicologic Pathology. 36 (2002):330-44.

18. Hubbs AF, et. al.. "Respiratory and olfactory cytotoxicity of inhaled 2,3-pentanedione in Sprague-Dawley rats." American Journal of Pathology. 181 (2012):829-44.

19. Morgan DL, et. al. "Respiratory toxicity of diacetyl in C57BL/6 mice." Toxicological Sciences 103 (2008):169-80.

20. Morgan DL, et al.  "Bronchial and bronchiolar fibrosis in rats exposed to 2,3-pentanedione vapors: implications for bronchiolitis obliterans in humans." Toxicologic Pathology. 40(2012):448-65.

21. NIOSH, (2016). Criteria for a recommended standard: occupational exposure to diacetyl and 2,3-pentanedione. U.S. Department of Health and Human Services (DHHS), National Institute for Occupational Safety and Health (NIOSH) Publication No. 2016-111, (October 2016).

22. The Detoxification System. Part III: Sulfoxidation and Sulfation. by Mark J Donohue

23. Barlow J., Johnson J.A.P., Early Life Exposure to Phenols and Breast Cancer Risk in Later Years,  Breast Cancer and The EnvironResearch Centers, 11/7/2007

24. Champe P.C., Harvey R.A., Ferrier D.R., Lippincott’s Illustrated Reviews - Biochemistry Edition 4, Lippincott Williams & Wilkins (2008)

25. Coffee C.J., Quick Look Medicine: Metabolism, Hayes Barton Press, (1999)

26. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride and Sulfate, The National Academies Press (2004)

27. Emery P., Bradley H., Gough A., Arthur V., Jubb R., Waring R., Increased prevalence of poor sulphoxication in patients with rheumatoid arthritis: effects of changes in the acute phase response and second line drug treatment, Annals of the Rheumatic Diseases, 51: 318 – 320 (1992)

28. Florin T., Neale G., Gibson G.R., Christl S.U., Cummings J.H., Metabolism of dietary sulphate: absorption and excretion in humans, Gut, 32: 766 -773 (1991)

29. Gandhi,N.S., Mancera R.L., The Structure of Glycosaminoglycans and their Interactions with Proteins, Chemical Biology and Drug Design, 72 (6): 455-482 (2008)

30. Gamage N., Barnett A., Hempel N., Duggleby R., Windmill K., Martin J., and McManus M., Human Sulfotransferases and Their Role in Chemical Metabolism, Toxicological Sciences, 90 (1): 5 – 22 (2006)

31. Ghazali R.A., Waring R.H., The effects of flavonoids on human phenolsulphotransferase: potential in drug metabolism and chemoprevention, Life Sciences, 65(16): 1625-1632 (1999)

32. Gullsten H., Significance of Polymorphism in CYP2A6 Gene, Department of Pharmacology and Toxicology, University of Oulu, Finland, (2000) Gunnison A.F., Jacobsen D.W., Sulfite Hypersensitivity: A Critical Review, CRC Critical Reviews in Toxicology, 17 (3): 185 – 214

33. Harris R.M., Waring R.H., Dietary Modulation of Human Platelet Phenolsulphotransferade Activity, Xenobiotica, 26 (12): 1241 – 1247, (1996)

34. Harries R.M., Picton R., Singh S., Waring R.H., Activity of Phenolsulfotransferases in the Human Gastrointestinal Tract, Life Sciences, 67: 2051 – 2057 (2000)

35. Heafield M.T., Fearn S., Steventon G.B., Waring R.H., Williams A.C., Struman S.G., Plasma Cysteine and Sulphate levels in patients with Motor Neurone, Parkinson’s and Alzheimer’s Disease, Neuroscience Letters, 110: 216 – 220 (1990)

36. Hibbs J, Biotransformation of Xenobiotics, Environmental Medicine, Toxicology and Detoxification Class, Bastyr University Hodgson E., A Textbook of Modern Toxicology – Third Edition, Wiley & Sons, Inc. (2004)

37. Klaassen C.D., Boles J.W., The Importance of 3’-phosphadenosine 5’-phosphosulfate (PAPS) in the Regulation of Sulfation, The Journal of the Federation of American Societies for Experimental Biology (FASEB), 11: 404 – 418 (May 1997)

38. Liska D.A., Lyon M., Jones D.S., Detoxification and Biotransformational Imbalances, Explore: The Journal of Science and Healing, 2(2): 122-140 (2006)

39. Janaky R., Varga V., Hermann A., Saransaari P., Ojo S.S., Mechanisms of L-Cysteine Neurotoxicity, Neurochemical Research, 25 (9/10): 1397-1405 (2000)

40. Liska D.J., The Detoxification Enzymes, Alternative Medicine Review, 3(3):187 – 198 (1998)

41. Pesticides and Toxic Substances, Registration Eligibility Document FACTS – Sulfur, United States Environmental Protection Agency, May (1991)

42. Maddey W.C., Gastroenterology and Hepatology: The Liver vol. 1, Current Medicine (1996)

43. Magee E.A., Curno R., Edmond L.M., and Cummings J.H., Contribution of dietary protein and inorganic sulfur to urinary sulfate, American Journal of Clinical Nutrition, 80 (1): 137 – 142 (2004)

44. Managing Biotransformation: The Metabolic, Genomic, and Detoxification Balance Points, The Proceedings From the 13th International Symposium of The Institute for Functional Medicine (2006),

Molybdenum, Alternative Medical Review, (June 2006)

45. Morris M.E., Levy G., Absorption of Sulfate from Orally Administered Magnesium Sulfate in Man, Clinical Toxicology, 20 (2): 107 – 114 (1983)

46. Moss M., Purines, Alcohol and Boron in the Diets of People with Chronic Digestive Problems, Journal of Nutritional & Environmental Medicine, 11: 23-32 (2001)

47. Moss M., Waring R.H., The Plasma Cysteine/Sulphate Ratio: A Possible Clinical Biomarker, Journal of Nutritional & Environmental Medicine 13(4): 215 – 229 (2003)

48. Murch S.H., MacDonald T.T., Walker-Smith J.A., Levin M., Lionetti P., Klein N.J., Disruption of Sulphated glycosaminoglycans in intestinal inflammation, The Lancet, 341 (8847): 711 – 714, (1993)

49. Murray R.K., Keeley F.W., Harper’s Illustrated Biochemistry, Chapter 48: The Extracellular Matrix, The McGraw-Hill Companies, (2009)

50. Osman L.P., Mitchell, S.C., Waring R.H., Cysteine, its Metabolism and Toxicity, Sulfur Reports, 20 (2): 155 – 172 (1997)

51. Parson R.B., Waring R.H., Ramsden D.B., Williams A.C., Toxicity of Cysteine and Cysteine Sulphinic Acid to Human Neuronal Cell Lines, Journal of Neurological Sciences, 152(1): S62-S66 (1997)

52. Pean A., Steventon G.B., Waring R.H., Foster H., Sturman S., Williams A.C., Pathways to Cysteine Metabolism in MND/ALS, Journal of the Neurological Sciences, 124: 59 – 61 (1994)

53. Scadding G.K., Ayesh R., Brostoff J., Mitchell S.C., Waring R.H., Smith R.L., Poor Sulfoxidation ability in Patients with Food Sensitivity, British Medical Journal, 297: 105 – 107 (1988)

54. Stipanuk M.H., Dominy J.E., Lee I.J., and Coloso R.M., Mammalian Cysteine Metabolism: New Insights into Regulation of Cysteine Metabolism, The Journal of Nutrition, 136:1652S – 1659S (2006)

55. Stipanuk M.H., Ueki I., Dominy J.E., Simmons C.R., and Hirschberger L.L., Cysteine Dioxygenase: a robust system for regulation of cellular cysteine levels, Amino Acids, 37(1): 55-63 (2008)

56. Stipanuk M.H., Sulfur Amino Acid Metabolism: Pathways for Production and Removal of Homocysteine and Cysteine, Annual Review of Nutrition, 24: 539 – 577 (2004)

57. Van der Kraan P.M., Vitters E.L., De Vries B.J., Van den Berg W.B., High Susceptibility of Human Articular Cartilage Glycosaminoglycan Synthesis to Changes in Inorganic Sulfate Availability, Journal of Orthopaedic Research, 8 (4): 565 – 571 (1990)

58. Waring R.H., Klovrza L.V., Sulphur Metabolism in Autism, Journal of Nutritional and Environmental Medicine, 10: 25-32 (2000)

59. Waring R.H., Klovrza L.V., Harris R.M., Diet and individuality in detoxification, Journal of Nutritional and Environmental Medicine, 16(2): 95-105 (2007)

60. Wilkinson L.J., Waring R.H., Cysteine Dioxygenase: modulation of expression in human cell lines by cytokines and control of sulphate production, Toxicology in Vitro, 16(4): 481-483 (2002)

61. Woolsey P., Cysteine, Sulfite, and Glutamate Toxicity: A Cause of ALS?, The Journal of Alternative and Complementary Medicine, 14 (9): 1159 – 1164 (2008)