by Dr. Hildegarde Staninger®, RIET-1
© July 1, 2013
ACETAMINOPHEN & PARACETAMOL and THEIR REACTION TO GLUTATHIONE
Recently, I co-authored a paper that is being published by the National Registry of Environmental ProfessionalsTM, Glenview, IL for their Professional Journal. The paper is entitled: “Glutathione and Its Role in the Biotransformation of Toxicants.” The paper is a must read paper for anyone who has been exposed to industrial solvents, venoms, hazardous materials, medications and other toxic chemical substances. The paper did not address a primary study that was conducted by J.R. Mitchell (1973) which specifically addressed the protective role of glutathione upon induced hepatic necrosis from exposure to the compound acetaminophen (paracetamol, the international nonproprietary name) an active ingredient in the medication Tylenol®.1, 2, 3a,b
The paper discusses the role of Xenobiotics and their metabolites. A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual. Specifically, drugs such as antibiotics are xenobiotics in humans because the human body does not produce them itself, nor are they part of a normal diet.
Natural compounds can also become xenobiotics if they are taken up by another organism, such as the uptake of natural human hormones by fish found downstream of sewage treatment plant outfalls, or the chemical defenses produced by some organisms as protection against predators.
However, the term xenobiotics is very often used in the context of pollutants such as dioxins and polychlorinated biphenyls and their effect on the biota, because xenobiotics are understood as substances foreign to an entire biological system, i.e. artificial substances, which did not exist in nature before their synthesis by humans. The term xenobiotic is derived from the Greek words ξένος (xenos) = foreigner, stranger and βίος (bios, vios) = life, plus the Greek suffix for adjectives -τικός, -ή, -ό (tic).4 a, b
Free reactive electrophilic intermediates of xenobiotics can produce damage to important cellular consitituents. Reduced gluathione and the glutathione S-transferase protect cells from this damage by capturing reactive electrophiles before they react at nuceleophilic sites critical to cell viability.5
The metabolism of acetaminophen, an analgesic that at high doses can produced hepatic necrosis, serves as an example of this protective system. A large body of work has shown that one of the principal ways in which acetaminophen produces its hepatotoxicity is via the reactive intermediate, N-acetyl-p-benzoquinone imines shown in Figure 1. This intermediate is apparently a soft electrophile that reacts readily with the strong, soft nucleophile glutathione. As long as the amount of glutathione present at the site of activation of acetaminophen is sufficient to bind the reactive intermediate, no toxicity ensues. However, as was demonstrated in a classic study by Mitchell et al.6, when glutathone is depleted by pretreatment with diethylmaleate, the benzoquinone imine covalently binds to tissue proteins resulting in tissue necrosis. Mitchell et. al.6 were among the first to propose that glutathione plays a fundamental role in protecting tissue against electrophilic attack by xenobiotics.7
Since these early studies demonstrating the protective role of glutathione, many compounds have been shown to form conjugates with glutathione. The protective interaction of glutathione and its primary sulfur dependent enzyme, glutathione-S-transferase play a major role in hormonal regulation of substrate supply to the small intestine. Insulin, glycogen, and catecholamines are the most important hormones that regulate the supply of glucose, fatty acids, and ketone bodies in most tissue. Early studies by W.C. Hulsmann concluded that the direct effect of these hormones on small intestinal epithelium may be modest or negligible, while interaction of streptozotocin-diabetic rat, showed the vascularly profused small intestine diminished glucose utilization. This, however, is probably due to the glucose sparing action of fatty acids and ketone bodies upon intestinal energy metabolism, because of the observation that in diabetes the rate of lactate formation is not decreased.8 a,b, 9
It is very important to note that glutathione plays a major role in detoxification, walling up the toxicants and adding a chain of beneficial mechanisms need to protect one from the chronic effects of hormones, such as thyroid hormones and glucocorticoids that are further stimulated or inhibited upon exposure to thiols/mercaptans.10
1) Staninger, Hildegarde and Daniel F. Farrier. Glutathione and Its Role in the Biotransformation of Toxicants. Journal of the National Registry of Environmental Professionals. Glenview, IL © June 28, 2013.
2) Sacarello, Hildegarde and Scott J. Evans. Genetic Cancer Risk Assessment of Electrophilic Hydrocarbon Mixtures in Subsurface Water Supplies. US EPA Agency: Research and Development. Symposium on short-Term Genetic Bioassays in the Evaluation of Complex Environmental Mixtures. Hotel Europa. Chapel Hill, North Carolina. March 27-29, 1984
3) (a) Hayes, A. Wallace. Principles and Methods of Toxicology, Second Edition. Chapter 2: Metabolism: A Determinant of Toxicity by J. Donald deBethizy and Johnnie R. Hayes. Raven Press, Ltd., New York, New York © 1989 pgs 29-69.
(b) Mentuccia, Roberto and Hildegarde Staninger. Increase or Boost Your Metabolism. Integrative Health Systems®, LLC. Los Angeles, CA © June 7, 2011
5) Mitchell, J.R. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exp. Ther., 187: 211-217, © 1973
6) Mohandas, J., Duggin, G.G., Horvath, J.S. and D.J. Tiller. Metabolic oxidation of acetaminophen (paracetamol) mediated by cytochorme P-450 mixed-function oxidase and prostaglandin endoperoxide synthetase in rabbit kidney. Toxicol. Appl. Pharmacol. 61:252-259.
7) Morgan, E.T., and M.J. Coon. Effects of cytochrome b5 on cytochrome P-450 catalyzed reactions: Studies withmanganese substituted cytochrome b5. Drug Metab. Dispos., 12: 358-364.
8) (a) Hulsmann, W.C. Abnormal stress reactions after feeding diets rich in (very) long chain fatty acids: high levels of corticosterone and testosterone. Mol. Cell. Endocrinol., 12: 1-8 (C) 1978
(b) Hulsmann, W.C. Energy metabolism in different preparations of rat small intestinal epithelium. In: Intestinal Permeation. Proceedings of the Fourth Workshop Conference Hoescht, edited by M. Kramer and F. Lauterbach, pp. 229-239. Excerpta Medica Intern. Congress Series 391, Excerpta Medica, Amsterdam.
9. Lamers, J.M.J. and W.C. Hulsmann. The effects of fructose on the stores of energy-rich phosphate in rat jejunum in vivo. Biochim. Biophys. Acta. 313: 1-8. © 1973
10. Schille, Carol M. Intestinal Toxicology. Target Organ Toxicology Series. Editor-in-Chief Robert L. Dixon. Raven Press, Ltd. New York, New York © 1984
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4/3/12 – FromTheDeskOfDrHildy: Series 3 – Poison’s My Game! What’s Yours? Nano Crystals and Modified Food Starches
© April 2, 2012
Series 3: Poison’s My Game! What’s Yours?
Nano Crystals and Modified Food Starches
I have been asked by several of my associates to condense this particular blog into terms that the average reader may relate to in their home, work environment or within their everyday life style. Well, if anyone knows me, sometimes it is hard to candy coat a technical piece, make it easier to understand or try to explain something technical to a non-technical minded person – so here goes.
Modified food starch is a term used in industry for any food starch that has something added to it or changed from its original form. Food starches come from potatoes, corn and other similar produce that has a high starch yield in its chemical composition. You may use corn starch to thicken your gravies, make fruit pie filling Read the rest of this entry →
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4/2/12-FROM THE DESK OF DR. HILDY-Series 2- BioEthnoticity and Nanotechnology – Cinnabar and Nanocheops
© March 6, 2012
Series 2: BioEthnoticity & Nanotechnology
CINNABAR and NANOCHEOPS
Cinnabar was “truly one” with Qin Shibuangdi, First Emperor of the Ming-dynasty (ruled 221-210 BCE) and the earliest known imperial patron of alchemy, next to Rudolf the Great of Hapsburg in 1218 AD for Europe. Despite the time periods Confucian disapproval of both the First Emperor and his fondness of alchemy, the ingestion of gold – or, rather, the transformed gold- appears to have remained quite popular throughout the Han dynasty. However, most Han dynasty alchemists worked with cinnabar, sometimes with fatal results. Cinnabar (mercury sulfide) is an ore of mercury that is a deep vermilion in color. When heated, cinnabar produces liquid mercury, and further heating and combination of mercury and sulfur will in turn reproduce cinnabar (a cyclical transformation that particularly intrigued Chinese alchemists). Mercury was further amalgamated with other metals (gold and lead in particular) producing elixirs to be ingested. While cinnabar itself was non-toxic- indeed it still maintains a prominent place in traditional Chinese medicine –
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March 6, 2012 VITAMINS and MINERALS
I want to thank all of the readers of this blog/column for joining us here, for you will gain tidbits of information to help yourselves in your everyday life and reduce your exposure to toxic substances from our environment and other areas where exposures occur. Over the last 4 decades of gaining knowledge about vitamins and minerals, I have learned the important roles they serve in our physiology and cellular metabolic applications. Since the introduction of hazardous materials, toxic substances, exposures to mold, advanced nano materials and many other parameters that synergistically effect life’s cellular activities, all life has been affected to a maximum degree by their toxicological effects. These effects are many times subtle, due to the human body always trying to make up for something going on within its basic cell structure, tissues and organ systems.
I will be writing this blog/column to bring to my readers information I feel is important to know, learn and to utilize in your everyday life, because everyone must take care of themselves, then they can take care of others – especially their family members.
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