The Science Behind: 'Synthergine - Liver Protectant'

This article will examine the potential contributions to health and well being of each of the ingredients that make up Synthergine™:

  1. Arginine Hydrochloride
  2. Lysine Hydrochloride
  3. Methionine Hydrochloride
  4. Sodium Glucuronate
  5. Di-isopropylamine Dichloroacetate

Three ingredients are amino acids. It is appropriate to ask why one would need to administer specific amino acids when they are present in protein therefore this article will spend time addressing the failure of protein to engage some of the pharmacological properties of amino acids. In fact increasing the dietary protein intake to a high level will lead to a reduction in the availability of some amino acids.

The article will spend time discussing the ability of a combination of Arginine and Lysine to reduce whole body stress and cortisol levels. The ability of this combination to reduce stress induced cortisol may be far more significant then any of their specifically defined detoxification properties.

The fourth ingredient Sodium Glucuronate aids the elimination of various compounds by making them more easily eliminated through urination. Among those eliminated compounds are hormones.

While many people are of the belief that they are careful with the types of medications and chemicals they ingest few understand that they may be engaged in an activity that reduces the liver’s ability to metabolize hormones. That activity is specifically related to the “in plasma” profile of exogenously administered growth hormone. The non-pulsatile elevation of growth hormone or even the less pulsatile pattern that comes as we age has the effect of creating a feminized secretory pattern which will dramatically alter the ability of the liver to metabolize drugs and hormones.

Although this may seem a bit out of place I believe it is very much worth our while to examine before looking at the specific actions of Sodium Glucuronate.

The final ingredient in the list is Di-isopropylamine Dichloroacetate. This article is compelled to examine the toxicity and safety of this compound because early studies failed in their methodology and wrongfully arrived at a conclusion that this compound is potentially mutagenic. Like a great many things in the age of Google the wrongful conclusion is probably more oft repeated then the conclusions that neither pure Diisopropylamine nor pure Dichloroacetate is mutagenic. In untainted forms they were deemed safe.

This allows us to proceed to examine the actions of Di-isopropylamine Dichloroacetate in reducing specific liver damage.

We will conclude the article by returning to an amino acid, methionine. We will examine its role in limiting liver injury brought about by an increase of a liver enzyme and its protective role in preventing fibrosis and liver cell death.

All of these topics will underscore the need for balance.

Amino Acids – inducing pharmacological responses

Amino acids have specific pharmacological properties that are often lost or diluted when they are ingested together with other amino acids. To obtain the pharmacological levels necessary to achieve a benefit high levels of protein would need to be ingested. Unfortunately high levels of protein are inadequate to the task not because they fail in the attempted provision of the quantity needed but rather because high protein intake fails in the delivery.

Whole foods or whole-protein powder or tablets of free amino acids may present the desired quantity of amino acids to the liver but there it is processed by the liver over a period of time. This means that more of the amino acids will be catabolized to urea rather then reach systemic circulation. Bypassing the initial pass through the liver in favor of sublingual intake and absorption through the gastric and intestinal mucosa will increase the concentration of amino acid that makes it into the systemic circulation as will all administrations that bypass the liver.

However the problem does not end once the amino acids make their way into circulation. Amino acids compete for transport into cells with the limited availability of the amino acid transport system that shuttle amino acids across the cellular membrane into cells. While there are several types of transporters for different classes of amino acids they can become saturated when presented with a large quantity of amino acids.

None of this is specifically limiting to normal physiological functioning but can be if the pharmacological property of an amino acid or two is desired at a specific point in time.

Changes in protein intake lead to metabolic responses that induce amino acid balance. Increasing dietary protein level above a threshold leads to a reduction of amino acid availability. The body increases amino acid catabolism following high-protein feeding as a method of preventing the accumulation of some amino acids, primarily the aromatic amino acids. Aromatic amino acids are phenylalanine, histidine, tryptophan, and tyrosine.

These are amino acids that are indispensable to the brain. It takes the steps necessary to maintain physiological concentrations which means controlling the level of amino acids through the liver.

The “down regulation” is not instantaneous. During the first days on a high protein diet amino acid catabolism is not fully engaged and intake of large amounts of protein results in an imbalanced amino acid pattern that signals the brain to among other things depress appetite.

Briefly the aromatic amino acids phenylalanine and tyrosine are involved in the synthesis of two important neurotransmitters; dopamine and norepinephrine. However large amounts of phenylalanine in particular may affect blood pressure and bring on headaches.

Histidine is involved in neurotransmission activity in the central nervous systems as well as increasing the production of red and white blood cells. However large amounts can cause zinc deficiency.

Tryptophan is the precursor to Serotonin, a neurotransmitter in the brain.

From this brief description you can see that the brain has an interest in maintaining fairly stable levels of these amino acids.

Some of the regulatory mechanism involved also has an effect on the other amino acids. It has been demonstrated that during periods of prolonged high protein intake, liver concentrations of some amino acids are very much depressed even though via feeding their supply was plentiful. Catabolism and limitations in transport appear to be responsible. More specifically the amino acids threonine, serine and glycine which share the same metabolic pathway are depressed on high protein diets.

Glutamine may become limited however because of its endogenous synthesis bounces back quickly when a high protein diet is stopped. It appears that the decrease in lysine and histidine concentrations in muscle brought about by high protein diets are also quickly reversed.

But the liver metabolic pathway shared by threonine, serine and glycine is slow to respond. As a result levels of these amino acids may still be depressed more then seven days after a high protein diet is suspended.

I think it is worth noting the functions of threonine. Threonine aids in the synthesis of glycine and serine which in turn are beneficial in the production of collagen, elastin, and muscle tissue.Threonine directly helps build strong bones and tooth enamel and plays a role in wound healing by boosting the immune system.

It has been found to be beneficial in treating Lou Gherig’s Disease (ALS). Some research shows that symptoms of degraded nerve & muscle from Multiple Sclerosis (MS) may be alleviated with threonine treatment. As an immunostimulant it promotes the growth of the thymus gland.

In addition taurine an amino acid that appears to have a protective effect in cardiovascular disease has been found to be reduced by as much as 50% in plasma when high protein diets are given.

It would be important for everyone to takes steps not to continually depress these amino acids.

So high protein intakes are not the answer to achieving the amino acid concentrations necessary to bring out their pharmacological properties. The remedy is intake of specific amino acids during times when dietary protein is not elevated, via methods some of which will bypass the liver.

Arginine + Lysine reduces stress and cortisol levels: A Pharmacological Response

L-lysine has been found to reduce anxiety and normalize stress-induced hormonal responses in healthy individuals with high anxiety 1. When it is used together with L-Arginine it has been found to block stress-induced abnormalities and manifestations of disease in laboratory and farm animals2-4.

The explanatory mechanism has been postulated to relate to Lysine’s ability to act as both a partial serotonin receptor antagonist 5,6 and simultaneously as a partial benzodiazepine agonist7,8.

This research was recently carried over into healthy humans in a study that tested the combined ability of L-lysine and L-arginine to reduce anxiety, stress and stress hormones in response to laboratory induced trauma9.

Human Study

In this study carried out by Smriga (2007), they had fifty healthy people who had perceived stress in their lives orally ingest 1.32 grams of L-lysine HCL and 1.32 grams of L-arginine twice a day (a total of 2.64 of each per day) for seven consecutive days. On the seventh day participants where subjected to stress testing to evaluate mental stress. Cortisol and chromogranin-A were measured in saliva. These measurements had been done prior to treatment as well.

Cortisol is a hormonal marker of the hypothalamo-pituitary-adrenal axis. Chromogranin-A is a protein found in adrenergic neurons. This protein directly reflects stress response and “sympathetic tone”. The Sympathetic Nervous System is a part of the nervous system that is always active to some degree and becomes more active during times of stress. This state is called the “sympathetic tone”.

High base cortisol and increased base “sympathetic tone” lead to psychological disease induction and blunt normal responsiveness of both the hypothalamo-pituitary-adrenal and sympathetic nervous system to stress exposure. Anxiety is a reflection of this state and long term health problems can occur with prolonged exposure to this state.

After these tests were given to establish base levels the participants were exposed to a stress-filled environment for 20 minutes to increase mental stress. They used loud speakers and increasing frequency of beats per minute to induce mental stress and then retested the participants.

They then placed them in a relaxing environment for 20 more minutes and tested them a final time.

They found that the exposure to the stress environment increased anxiety in the placebo subjects by about 10% but this increase was significantly blunted by Lysine/Arginine treatment.

The authors had postulated based on their previous studies that a reduction in base cortisol and chromogranin-A by Lysine/Aginine would lower anxiety and improve the response of the hypothalmo-pituitary-adrenal axis and Sympathetic Nervous system to acute mental stress.

They found that in both men and women Lysine/Argine succeeded in blocking mental stress. While Lysine/Arginine was a significant anti-anxiety agent in both sexes declines in the two biomarkers do not account for the entire calming effect.

In men base values of cortisol and chromogranin-A declined significantly but this did not occur in women. Several factors such as lower salivary values in women, co-influence of menstrual cycle and the probable need to measure a more detailed time response in women likely account for the discrepancy.

In the Lysine/Arginine group of males chromogranin-A reacted to the stress event and returned to base levels within 20 minutes while the placebo males continued to experience high levels both during and after the mental stress events.

Pharmacological effects of Arginine/Lysine

The participants in the study continued their normal dietary lifestyle which included about 5 to 6 grams of each amino acid from whole food protein sources. Yet as evidenced by the placebo group this did not induce the stess lowering effect. The addition of 50% more of each of those amino acids did trigger the positive effects.

In addition to a lowering of cortisol and curbing sympathetic tone, the authors believed that Arg/Lys might also have triggered pharmacological-like effects in the gut and brain through the benzodiazepine, serotonin or amino acid-specific receptors.

To further underscore all of this another study recently found that mental fatigue triggered by a single mental test significantly decreased plasma lysine levels which persisted for at least 24 hours 10.

The safety profiles of these two amino acids are well established and present no evidence of toxicity 11.

A note on suppression of cortisol

Over production of cortisol and prolonged elevations as seen under stressful conditions can lead to health problems. One of the effects of increased cortisol is an inhibition of protein synthesis which means that protein degradation will continue uncountered resulting in net protein breakdown. Elevated levels of cortisol also inhibit the transport and uptake of amino acids into tissue 12.

The accumulated rise in cortisol if unchecked begins to significantly affect muscle tissue after approximately 4 hours 13. Internal and external stress events can raise these levels and suppress the uptake of crucial amino acids for long periods of time which will result in some loss of muscle tissue if steps are not taken to counter the rise in central nervous system activity and pituitary & adrenal cortisol activity.

The co-administration of L-lysine HCl & L-Arginine is able to shutdown that potentiality.

References:

1 – Jezova D, Makatsori A, Smriga M, Morinaga Y and Duncko R , Subchronic treatment with amino acid mixture of L-lysine and L-arginine modifies neuroendocrine activation during psychosocial stress in subjects with high trait anxiety, Nutr Neurosci 8, 155-160 (2005)
2 – Smriga M and Torii K , Prolonged treatment with L-lysine and L-arginine reduces stress-induced anxiety in an elevated plus maze, Nutr Neurosci 6, 125-128 (2003)
3 – Smriga M and Torii K, Metabolic interactions between restraint stress and L-lysine: the effect on urea cycle components, AAmino Acids 24, 435-437 (2003)
4 – Srinongkote S, Smriga M, Nakagawa K and Toride Y, A diet fortified with L-lysine and L-arginine reduces plasma cortisol and blocks anxiogenic response to transportation in pigs, Nutr Neurosci 6, 283-289 (2003)
5 – Hasler WL, Lysine as a serotonin receptor antagonist: using the diet to modulate gut function, Gastroenterology 127, 1004-1006 (2005)
6 – Smriga M and Torii K, L-lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats, Proc Natl Acad Sci USA 100, 15370-15375 (2003)
7 – Chang YF, Wing Y, Cauley RK and Gao XM, Chronic L-lysine develops anti-pentylenetetrazol tolerance and reduces synaptic GABAergic sensitivity, Eur J Pharmacol 233, 209-217 (1993)
8 – Chang YF and Gao XM , L-lysine is a barbiturate-like anticonvulsant and modulator of the benzodiazepine receptor, Neuroch Res 20, 931-937 (1995)
9 – Smriga M, et al., Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans Biomedical Research Vol. 28 (2007) , No. 2 April pp.85-90
10 – Mizuno K, Tanaka M, Nozaki S, Yamaguti K, Mizuma H, Sasabe T, Sugino T, Shirai T, Kataoka Y, Kajimoto Y, Kuratsune H, Kajimoto O and Watanabe Y, Mental fatigue induced decrease in levels of several plasma amino acids, Journal of Neural Transmission, Volume 114, Number 5 / May, 2007
11 – Tsubuku S, Mochizuki M, Mawatari K, Smriga M and Kimura T, Thirteen-week oral toxicity study of L-lysine hydrochloride in rats, Int J Toxicol 23, 113-118 (2005)
12 – Kettelhut, IC, Endocrine regulation of protein breakdown in skeletal muscle, Diabetes/Metabolism Rev 4: 751-772 (1988)
13 – McNurlan, MA and Garlick, PJ, Influence of nutrient intake on protein turnover, Diabetes/Metabolism Rev 5: 165-189 (1989)

Exogenously administered Growth Hormone leads to feminized secretory pattern and altered steroid metabolism

Men and women release growth hormone (GH) in patterns unique to their sex. Adult men secrete growth hormone in a pulsatile pattern with well pronounced peaks of plasma growth hormone occurring approximately every 3.5 hours followed by periods without measurable growth hormone (GH off-time) lasting about two hours.

Male pulsatile GH release pattern

In contrast, adult females have a more frequent growth hormone release which results in near-continuous presence of GH in plasma.

Female continuous GH release pattern

These adult patterns of GH release are set during the first month of life by exposure to gonadal steroids, which program the hypothalamus and its regulation of pituitary GH secretion to behave in sexually distinct ways at the onset of puberty and during adulthood 1.

This difference in pattern has significant consequence primarily determined by the “off time” or period when no detectable GH is present in males or is elevated in females. This “off time”, a period when there is no (or very low) growth hormone present is required for the expression of male-specific liver enzymes, such as cytochrome P450 (CYP) 2C11 2. Without this off time those liver enzymes needed to metabolize male hormones do not get expressed to a significant degree. The reason for this failure appears to primarily result from the fact that the intracellular pathway STAT5b responsible for the synthesis of these enzymes needs time off. If it doesn’t get time off it fails to reset.

The following image will serve to give a quick understanding. Growth Hormone is a molecule that may be visualized as a peg which lands on a receptor where it flips a switch and sets things in motion. One of the things it sets in motion is an intracellular pathway known as signal transducer and activator of transcription 5b (STAT5b). This protein once activated moves to the cell nucleus and initiates the transcription of end product proteins such as liver enzymes. It then is deactivated returns to the receptor and is reactivated to again mediate transcription.

When a pulse of growth hormone activates growth hormone receptors it does so with a strong enough punch that STAT5b undergoes multiple rounds of activity during this single pulse. When a non-pulsatile more feminine continuous growth hormone “bleed” activates growth hormone receptors STAT5b activity is not as vigorous and this activity or mediating cycle is terminated more quickly.

GH receptor activity leads to Stat5b activity

When exogenous growth hormone is administered in a way that causes prolonged elevation of plasma growth hormone the GH pulse induced expression of male specific liver genes is reduced and if long enough completely abolished while the expression of female specific genes is significantly induced 3. This can primarily be attributed to the failure to give STAT5b an “off time” which reduces its activation and partially desensitizes it to growth hormone 4.

GH pulsation leads to greater Stat5b activity

The time period required to reset the STAT5b pathway after a GH pulse is two to three hours 5,6.

What does a reduction in STAT5b imply?

In male mice STAT5b deficiency leads to loss of the male-specific liver enzymes and loss of both puberty and adult male body growth pattern. In fact loss of STAT5b resulted in a substantial decrease in the expression of about 90% of male-specific liver genes 7,8. In females STAT5b gene disruption has only a modest effect on body growth rate and liver gene expression.

STAT5b disruption is associated with lower circulating IGF-I levels, elevated plasma GH, increased expression of prolactin receptor 9-11 and lower body growth rates 12.

Treatment with exogenous GH given in pulsatile fashion restores the expression of sex-dependent liver enzymes that are normally present in normal males. Exogenous GH pulses also stimulate body weight gain in males 7, 13. All of this underscores the requirement of STAT5b for both liver gene expression and body growth.

Which liver enzymes are effected and how does this contribute to “toxicity” ?

There is an entire class of liver enzymes known as Cytochrome P450. Within this general class are male and female specific forms. These enzymes metabolize steroids, fatty acids, lipophilic drugs (i.e. dissolve in fats), environmental chemicals and pollutants.

The creation of these enzymes is induced by various factors including growth hormone. Growth hormone regulates the expression of these Cytochrome genes in a sex-dependent manner. Pulsation of growth hormone secretion (a masculine pattern) results in creation of the male Cytochrome P450 isoforms while continuous growth hormone secretion (a feminine pattern) results in creation of the female Cytochrome P450 isoforms.

Pulsative GH Releases Male Liver Enzymes while Continuous GH Releases Female Liver Enzymes

The metabolism of foreign chemicals by Cytochrome P450 enzymes frequently results in successful detoxification of irritants however; the actions of P450 enzymes can also generate toxic metabolites that contribute to increased risks of cancer, birth defects, and other toxic effects 14.

Furthermore expression of many P450 enzymes is often induced by accumulation of a substrate. For example, liver concentrations of the female liver enzyme may be induced by a specific drug or hormone which must be metabolized. This may lead to a cascade of other liver enzymes expressing themselves in response to this activity 14.

Finally these enzymes often act on various substrates including saturated and unsaturated fatty acids, eicosanoids, sterols and steroids, bile acids, vitamin D3 derivatives, retinoids, and uroporphyrinogens. When they act on these substrates they may effect an oxidative, peroxidative or reductive change into small molecules which results in a new array of chemical structures 14.

The proper understanding of these things is simply the following. It is important to both liver and overall health to take steps to reduce imbalances in this entire class of enzymes and to the extent that imbalances do occur there may be consequences that at the very least require correction.

Specific Examples

The female P450 isoform CYP3A4 can be thought of as having a role in estradiol homeostasis. Specifically it hydroxylates estradiol at the 2, 4 and 16 alpha positions. It also catablyzes 6 beta-hydroxylation of testosterone which it converts to estradiol by the action of aromatase. This activity is welcome for mammary gland development and lactation if you are a female. But if you are a male with a lot of substrate in the form of testosterone you don’t want this enzyme to be active 15.

Yet patients suffering from acromegaly and men who are given continuous forms of GH treatment end up with greatly upregulated expression of this female liver enzyme 16,17. This female liver enzyme is suppressed by intermittent pulsatile GH 18.

The female P450 isoform CYP3A4 also metabolizes other steroids such as cortisol as well which is converted more rapidly in women then men 19.

Many of the male P450 isoforms have roles in testosterone metabolism such as CYP2C11 which hydroxylases testosterone and converts testosterone to androstenedione for use in resynthesis. This activity is lost when a female pattern of GH release is instituted.

The female GH release profile stimulates the full expression of testosterone 5 alpha reductase activity 20,21. In men with the substrate testosterone this female GH release profile can lead to a substantial conversion of testosterone to Dihydrotestosterone (DHT).

It is also thought that certain environmental triggers and food additives can trigger autoimmune diseases for those genetically predisposed. Alterations in GH release profile brought about by environmental factors make middle aged women more susceptible then men to such triggers as MSG and Aspartame in invoking auto-immune hepatitis 22.

The full treatment of this topic is beyond the scope of this review. This section was meant to underscore the fact that imbalances are created in ways not often considered. Health and a reduction in toxicity require countermeasures which could include the use of compounds such as the Arginine/Lysine combination to reduce cortisol or Sodium Glucuronate to bind and eliminate the byproducts of P450 enzymal activity. Of course another beneficial method would be to optimize sex specific GH release patterns rather then eliminate them.

References:

1 – Chowen JA, Frago LM, Argente J, The regulation of GH secretion by sex steroids. Eur J Endocrinol 151(Suppl 3):U95–U100 (2004)
2 – Waxman DJ, Pampori NA, Ram PA, Agrawal AK, Shapiro BH, Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450, Proc Natl Acad Sci USA 88:6868–6872 (1991)
3 – Thangavel C, Garcia MC, Shapiro BH, Intrinsic sex differences determine expression of growth hormone-regulated female cytochrome P450s, Mol Cell Endocrinol 220:31–39 (2004)
4 – Waxman DJ, Ram PA, Park SH Choi HK, Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein, Proposed role as an intracellular regulator of male-specific liver gene transcription, J Biol Chem 270:13262–13270 (1995)
5 – Gebert CA, Park SH, Waxman DJ, Regulation of signal transducer and activator of transcription (STAT) 5b activation by the temporal pattern of growth hormone stimulation, Mol Endocrinol 11:400–414 (1997)
6 – Ji S, Frank SJ, Messina JL, Growth hormone-induced differential desensitization of STAT5, ERK, and Akt phosphorylation, J Biol Chem 277:28384–28393 (2002)
7 – Holloway MG, Laz EV, Waxman DJ Co-dependence of growth hormone-responsive, sexually dimorphic hepatic gene expression on STAT5b and HNF4-alpha, Mol Endocrinol 20:647–660 (2006)
8 – Clodfelter K, Holloway MG, Hodor P, Park S-H, Ray WJ, Waxman DJ, Sex-dependent liver gene expression is extensive and largely dependent upon STAT5b: STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis, Mol Endocrinol 20:1333–1351 (2006)
9 – Norstedt G, Palmiter R, Secretory rhythm of growth hormone regulates sexual differentiation of mouse liver, Cell 36:805–812(1984)
10 – Kelly PA, The growth hormone/prolactin receptor family, Recent Prog Horm Res. 48:123–164 1993
11 – Noshiro M, Negishi M, Pretranslational Regulation of Sex-dependent Testosterone Hydroxylases by Growth Hormone in Mouse Liver, J Biol Chem 261:15923–15927 (1986)
12 – Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW, Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression, Proc Natl Acad Sci USA 94:7239–7244 (1997)
13 – Davey HW, Park SH, Grattan DR, McLachlan MJ, Waxman DJ, STAT5b-deficient mice are growth hormone pulse-resistant, Role of STAT5b in sex-specific liver p450 expression, J Biol Chem 274:35331–35336 (1999)
14 – Nebert Daniel W, Russell David W, Clinical importance of the cytochromes P450, THE LANCET • Vol 360 • October 12, 2002
15 – Yu AM, Fukamachi K, Krausz KW, Cheung C, Gonzalez FJ, Potential role for human cytochrome P450 3A4 in estradiol homeostasis, Endocrinology 146:2911–2919 (2005)
16 – Watkins PB, Turgeon DK, Jaffe CA, Ho PJ, Barkan AL, Pulsation frequency of growth hormone may mediate gender differences in CYP3A activity in man, Clin Res 41:132 (1993)
17 – Jaffe CA, Turgeon DK, Lown K, Demott-Friberg R, Watkins PB, Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans, Am J Physiol Endocrinol Metab 283:E1008–E1015 (2002)
18 – Dhir RN, Dworakowski W, Tangavel C, Shapiro BH, Sexual dimorphic regulation of hepatic isoforms of human cytochrome P450 by growth hormone, J Pharmacol Exp Ther 316:87–94 (2006)
19 – Inagaki K, Inagaki M, Kataoka T, Sekido I, Gill MA, Nishida M, A wide interindividual variability of urinary 6ß-hydroxycortisol to free cortisol in 487 healthy Japanese subjects in near basal condition, Ther Drug Monit 24:722–727 (2002)
20 – Shapiro BH, Agrawal AK, Pampori NA, Gender differences in drug metabolism regulated by growth hormone, Int J Biochem Cell Biol 1995;27:9–20
21 – Pampon NA, Shapiro BH, Gender differences in the responsiveness of the sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone profile, Endocrinology 1999;140:1245–1254
22 – Prandota, Joseph, Possible Pathomechanism of Autoimmune Hepatitis, American Journal of Therapeutics 10, 51–57 (2003)

Sodium Glucuronate

Sodium Glucuronate is the salt ester of Glucuronic acid. In the body the salt is usually quickly removed to form Glucuronic acid, therefore for purposes of this review they will be treated as equivalent. Glucuronic acid forms glycosidic bonds with substances in the body through a process known as glucuronidation. In doing so it enables the body to metabolize drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. The process of linking glucuronic acid to these compounds occurs primarily in the liver. Once linked these toxins and compounds become more water soluble and may be readily eliminated by the body through urination.

So Sodium glucuronate and Glucuronic acid enable the body to metabolize and eliminate substances it wants to get rid of. In addition Glucuronic acid by binding to certain hormones and lending its water soluble property may instead of elimination facilitate hormonal transport around the body. So Sodium glucuronate and Glucuronic acid are liver detoxifiers but serve other purposes as well.

Is exogenous administration safe?

Even though endogenous synthesis occurs, before discussing effectiveness it is appropriate to determine if exogenous administration of sodium glucuronate is safe. For that we turn to a body of studies that administered sodium glucuronate in newborn human infants. A series of four studies were published in 1959 and 1960 in which the administration of sodium glucuronate was administered to newborns born with high bilirubin and jaundice 1-4.

Bilirubin is mainly formed by the normal breakdown of haemoglobin. Haemoglobin carries oxygen in red blood cells. Bilirubin passes through the liver. It is then excreted as bile through the intestines. When this process is interrupted, excess bilirubin stains other body tissues yellow. Fatty tissues like skin, eye tissue and blood vessels are the most easily affected. Increased levels of bilirubin are linked with a range of illnesses and conditions. This includes jaundice associated with hepatitis and cirrhosis, anemia, Gilbert’s disease and sickle cell disease. Jaundice is common in babies. Very high levels in babies can cause permanent damage.

The hope of these studies was to eliminate excess bilirubin. The results were encouraging in one of the four studies, mixed in another and of no value in two. The reasons are specifically applicable to the unique condition of these disease states in infants and are not readily relevant to adults. However these studies administered Sodium glucuronate to more than fifty newborns. They would not have been allowed to do so had there been a safety concern. Follow up with these infants over a six months period revealed no problems related to administration of the compound. It is a safe compound.

Is exogenously administered Sodium glucuronate effective?

Buried in research papers written in Japanese, inside the archives of 1950’s Pharmaceutical companies with names like Chugai Pharmaceutical Company, Tokyo and in the nonpublic files of various academic institutions such as Kyushu University reside the results of a massive research campaign. A campaign designed for the most part to sate a wide spread curiosity. The inquiry spans the better part of five years during which Glucoronic Acid and its derivatives biological properties were examined in almost every living situation. Research conferences were held every year for at least five years during which researchers from laboratories in Japan gathered to exchange views and acquire information regarding the biochemical studies they had completed on glucornonic acid. These conferences were attended by more then 250 investigators almost exclusively Japanese.

At the 1959 conference forty-four original papers were presented. Thirteen of the papers focused on the biochemistry and physiology of glucuronic acid. Four focused on its growth promoting effect and twelve were exclusively devoted to detoxification of drugs, viruses and toxins. The remainder centered on the clinical uses of glucuronic acid.

If it were not for William H. Fishman from Tufts University School of Medicine very little would be known about this incredible research and we will rely in part on his fifty year old notes to summarize the experimental and clinical studies on detoxification that were presented at the fifth Glucuronic Acid Research Conference held at Sankei Kaikan, Tokyo in the summer of 1959.

At least two of the research papers presented were translated into English, published in the Japanese Journal of Pharmacology and readily available. That research sought to determine what effect if any exogenous sodium glucuronate would have on the very toxic morphine in lab animals.

It had already been reported that injected morphine conjugates with glucuronic acid and forms “bound morphine” 5.

In these two studies they found that injection of sodium glucuronate in advance of morphine bound to morphine and reduced its effect (toxicity). The higher the dose of sodium glucuronate the greater the inhibition of morphine’s effect. They engaged in an experiment to prove a direct relationship and measured free and bound morphine excreted into urine by the lab animal after morphine and morphine plus sodium glucuronate 6,7.

They found that sodium glucuronate bound to morphine and excreted it quickly. They even found that unbound morphine was excreted quicker along side its bound brethren. The exogenous administration of sodium glucuronate decreased the toxicity of morphine and significantly increased its excretion in urine. Although they believed that exogenous administration resulted in a conjugation of glucuronic acid (formed when sodium glucuronate loses the salt ester) with the morphine they held open the possibility that it accelerated the conjugation of endogenous glucuronic acid through some unknown mechanism 6,7.

Exogenously administered sodium glucuronate very efficiently becomes glucuronic acid 8 and is able to effectively bring about a detoxification of morphine and increase its elimination. It is a very effective compound and should be capable of detoxifying a great number of less hazardous toxins.

In other studies reported at the 1959 summit we find that * :

  • Imanaga stated that the increase in blood ammonia in patients with a portacaval shunt can be controlled with exogenous glucuronic acid;
  • Harashima (Keio University) observed increased urinary excretion of glucuronic acid in rabbits experimentally exposed to benzene and carbon disulfide;
  • Ito discussed his study on the use of glucuronic acid in the detoxification of 2,4-dinitrophenol (DNP);
  • Takatsu (University of Tokyo) discussed his work on the positive effect of sodium glucuronate on the toxicity of Shigella endotoxin, phenol, pyramine, and noradrenaline in the young mouse;
  • In the field of virology, Ogasawara et al. (Nagoya University) studied the effects of glucuronic acid salts on the activity of influenza virus PR8 and of Newcastle disease virus in producing pyrogenic skin lesions and pulmonary consolidation. On the whole, infectivity, hemagglutinin, and antigenicity of these two viruses were not affected significantly, but the toxicity (skin lesion, pulmonary consolidation) was prevented by preliminary treatment with glucuronolactone [a glucuronic acid derivative];
  • Coto et al. (University of Tokyo) observed the in vitro inhibition by glucuronic acid of mouse hepatitis virus, rabies virus, and Japanese encephalitis virus, with regard to their ability to infect the host mice;
  • Clinical studies included work on the effects of glucuronic acid on steroid hormone excretion during pregnancy (Moriyama et al.);
  • Studies on glucuronic acid metabolism of newborn infants (Iwanami et al.);
  • Three separate investigations on glucuronic acid interrelationships with adrenal cortical function (Tokita et al., Oshima et al., and Kawai et al.);
  • Two reports on a therapeutic effect of glucuronolactone in diabetes mellitus (Katsuki et al. and Matsuoka et al.);
  • The treatment of epidemic hepatitis with glucuronic acid (Kosaka et al.);
  • The influence of glucuronolactone on experimental liver injury induced by Penicillium islandicum Sopp poisons (Suzuki et al. and Uraguchi et al.)

Exogenously administered sodium glucuronate is an effective and safe compound capable of significantly aiding the elimination of potentially harmful compounds.

References:

1 – Jeliu, Gloria, Administration Of Glucuronic Acid To Icteric Newborn Infants, Pediatrics 1959;23;92-97
2 – Schwob, Marianne, The Influence Of Sodium Glucuronate On Hyperbilirubinemia Of The Newborn—Further Observations, Pediatrics 1960;25;686-689
3 – Danoff, Stuart, The Treatment Of Hyperbilirubinemia Of The Newborn With Sodium Glucuronate, Pediatrics 1959;23;570-577
4 – Dwyer, J. Henry, The Administration Of Sodium Glucuronate To Jaundiced Newborn Infants, Pediatrics 1959;24;400-403
5 – Woons, L.A., J. Pharmacol. 112, 158 (1954)
6 – Seiji Otobe, Studies On The Conjugation Of Glucuronic Acid With Morphine Part 1 : Effects Of Exogenous Glucuronic Acid Upon The Analgesia Due To Morphine In Mice, Japanese Journal of Pharmacology 9, 100-104 (1960)
7 – Seiji Otobe, Studies On The Conjugation Of Glucuronic Acid With Morphine Part 2 : Influence Of Exogenous Glucuronic Acid Upon The Excretion Of Free And Bound Morphine In Urine Of Rabbits, Japanese Journal of Pharmacology 9, 105-108 (1960)
8 – Packham M., Butler, G. C., The Fate Of Injected Sodium Glucuronate And Glucurone In The Rat, The Journal of Biological Chemistry 1954 Apr;207(2):639–646

* – Recollections of William H. Fishman

Di-isopropylamine Dichloroacetate

There are two compounds in Synthergine™ that may specifically reduce the potential for hepatic injury in the form of fibrosis and cell death. Cell death or necrosis is the final result of obstruction of blood supply following an ongoing incursion of fat infiltrating the liver. The preventative compound Methionine Hydrochloride will be discussed in this regard in the next section. This section is devoted to a curing compound Di-isopropylamine Dichloroacetate.

Di-isopropylamine Dichloroacetate is a compound that can be used to reverse fatty acid liver disease.

In 2005 a clinical study 1 set out to investigate the effectiveness and safety of diisopropylamine dichloroacetate in the treatment of nonalcoholic fatty liver diseases. One hundred twenty three patients who had this disease were randomly assigned to 2 groups treated with either a high dosage (120 mg/d) or a low dosage (60 mg/d) of diisopropylamine dichloroacetate for 8 weeks.

At the end of the 8 week treatment period, the overall improvement of clinical symptoms in the high dosage and in the low dosage group was 87.8% and 79.6%, respectively. These symptoms included fatigue, pain in the upper right abdomen and weight loss 1.

An alanine aminotransferase (ALT) test measures the amount of this enzyme in the blood and is used to determine if the liver is damaged or diseased. Low levels of ALT are normally found in the blood. But when the liver is damaged or diseased, it releases ALT into the bloodstream, which makes ALT levels go up. Most increases in ALT levels are caused by liver damage 1.

The study found that ALT which was initially high normalized in 55.7% and 69.4% of the cases in the two groups as a result of Di-isopropylamine Dichloroacetate treatment. Serum lipids, primarily LDL (low-density lipoprotein) and Triglycerides were lowered in 67.2% and 67.7% of the cases in the two groups. Ultrasound grading of the level of liver alteration severity was measured and found to be lowered in 51.7% and 43.5% in the two groups 1.

The differences found between the two groups were of no statistical significance so the lower dose was sufficient to achieve the positive effects. No severe adverse drug reactions were found 1.

The study concluded that “Diisopropylamine dichloroacetate could be used as a safe and effective drug in the treatment of nonalcoholic fatty liver diseases 1.”

The safety of Di-isopropylamine Dichloroacetate

This article is compelled to examine the toxicity and safety of this compound because a few early studies failed in their methodology (i.e. tainted samples) and wrongfully arrived at a conclusion that this compound is potentially mutagenic. In untainted forms they were deemed safe.

Dichloroacetate

The most complete study on the safety of Dichloroacetate (DCA), Absence of Mutagenic Effects of Sodium Dichloroacetate, Fox, Anthony W., Fundamental And Applied Toxicology 32, 87-9 5 (1996) was undertaken so that clinical studies exploring the therapeutic potential could be undertaken in a clinical setting. Dichloroacetate has the potential to play a role in the treatment of stroke and head injury and in the treatment of disease states that result in elevated lactate concentrations.

This study went far beyond previous studies which undertook a single reverse mutation test on E. Coli called an Ames test. This study included an Ames test, a mutation test in mouse lymphoma cells, a clastogenesis test in Chinese hamster ovary cells and erthroid micronucleation after in vivo dosing in male & female rats.

In each of these they found no evidence of mutagenic activity attributable to Dichloroacetate.

They then examined previous studies which used an Ames test only and had reached inconsistent conclusions. The results of their examination revealed that in those instances where a mutagenic effect was found the researchers had introduced differing impurities into the test material. One such study which showed both a mutagenic effect and no mutagenic effect appears to have included an impurity in the redistillation of their liquid acid with a boiling point similar to the acid of the study compound Dichloroacetate and so the impurity remained.

They went on to note the other studies that found no mutagenic activity from their Ames tests and stated that “previously published Ames test results do not convincingly demonstrate that dichloroacetate can cause reverse mutations.”

The authors concluded,

“The present studies have examined a wider variety of mutagenic mechanisms than previous reports. The objective here was to meet the modern standards established by the International Conference on Harmonization. The consistently negative results for DCA among these diverse types of assay, as well as (when appropriate) between assays with and without activation, provides a comprehensive basis for concluding that DCA from this source (which is relatively pure compared to some other sources) is not mutagenic.”

Diisopropylamine

At about the same time as the aforementioned study was being conducted; a comprehensive study on the safety of Diisopropylamine was published. Final Report on the Safety Assessment of Diisopropylamine, F. A. Andersen, Journal of the American College of Toxicology 14(3):182-192 (1995) examined the safety of Diisopropylamine primarily because of its widespread use in the cosmetics industry. The study found no mutagenic activity and suggested that a study conducted 13 years prior which reached an opposite conclusion did so because of an impurity in the Diisopropylamine that was used.

The studies undertaken on mutagenic activity in this study were far more extensive then previous studies and each test was completed in triplicate. No toxicity was found.

The authors concluded,

“On the basis of the data presented in this report, the CIR Expert Panel concludes that Diisopropylamine is safe as a cosmetic ingredient as presently used.”

They did note that Diisopropylamine should not be used in products containing N-nitrosating agents which could form nitrosamines which are potentially harmful.

So what is a “Nitrosating Agents”?

Nitrosating Agents include Sodium Laureth Sulfate, Ammonium Laureth Sulfate, Sodium Methyl Cocoyl Taurate which are products used as engine degreasers and in personal care products that foam; Sodium Lauryl Sulfate, Ammonium Lauryl Sulfate frequently disguised in semi-natural cosmetics with the explanation “comes from coconut”; DEA (diethanolamine), MEA (Monoethanolamine), TEA (triethanolamine) used in cosmetics to adjust the pH as a basis for a cleanser as well as Cocoyl Sarcosine, Imidazolidinyl Urea, Formaldehyde, Hydrolysed Animal Protein, Lauryl Sarcosine and Quaternium-7, 15, 31, 60.

None of this has anything to do with Synthergine™ because those chemicals are not present in Synthergine™. For the sake of sating the curious mind lets list end product nitrosamines which are the compounds that can be potentially harmful and cause mutagenic activity. They include:

  • Fried bacon
  • Cured meats
  • Beer
  • Nonfat dry milk
  • Tobacco products
  • Gastric juices
  • Rubber products
  • Rubber manufacturing
  • Metal industries
  • Pesticide production and use
  • Certain cosmetics
  • Certain chemical manufacturing

To the extent you are able, it is best to limit ingestion of these items and avoid the chemicals associated with those industries and I surmise with gastric juices it is best to not have an excess.

Juice extracted from Kiwi and ascorbic acid are two items capable of inhibiting n-nitrosation and should probably be used if you are exposed to any of the chemicals listed previously 2.

In conclusion pure Di-isopropylamine Dichloroacetate is a safe non-toxic compound when it is not part of a product containing N-nitrosating agents.

References:

1 – Lu LG, Zeng MD, Diisopropylamine dichloroacetate in the treatment of nonalcoholic fatty liver disease: a multicenter random double-blind controlled trial, Chinese journal of hepatology 13(2):92-5, 2005 Feb
2 – Advances in Food Research By C. O. Chichester, B S Schweigert, Academic Press (January 1988) page 62

Methionine Hydrochloride

Like Arginine & Lysine Methionine is an amino acid. It is a lipotropic compound which means it increases the export of fat from the liver. When estrogen levels are high, the body requires more methionine. Higher levels of estrogen reduce bile flow through the liver and increase bile cholesterol levels. Methionine helps deactivate estrogens and normalizes the flow of fat from the liver.

Methionine is readily converted to Cysteine. Cysteine has a high affinity for binding metals and other toxins which enables it to detoxify, chelate, and remove harmful metals and free radicals from the body. These things are important.

I wanted to emphasize two studies which fit within some of the general themes of this article.

The first study details how a derivative of methionine can protect the liver from the bad effects of a liver enzyme. Previously we explored how the pattern of growth hormone release determines whether male or female specific liver enzymes will be created. Creating liver enzymes inappropriate to ones sex can cause problems. We often view these problems as resulting from toxins that liver enzymes are unable to metabolize. However in some instances the liver enzymes themselves can cause liver injury.

In S-adenosyl methionine protects ob/ob mice from CYP2E1-mediated liver injury, Aparajita Dey, Andres A. Caro, and Arthur I, Cederbaum, Am J Physiol Gastrointest Liver Physiol 293: G91–G103, 2007 the expression of the liver enzyme CYP2E1 was shown to potentiate liver injury in obese mice but not lean mice through its ability to generate oxidative stress.

Methionine acts as a methyl donor in biochemical pathways which can be converted to SAMe (S-adenosyl methionine). SAMe can prevent CYP2E1 induced toxicity 1,2. In addition mice fed a diet deficient in methionine and choline developed fatty liver. Humans who have developed cirrhotic liver have been shown to have both an impaired metabolism of methionine and reduced synthesis of SAMe in the liver 3,4.

The study found that SAMe acted to protect the liver from injury but also that the method used to increase CYP2E1 expression decreased endogenous SAMe levels. The exogenous administration of SAMe more then compensated for the loss by elevating the liver SAMe levels to higher concentrations then normal. This exerted the protective effect.

The second study in addressing the protective role of Methionine underscores the need for balance. Both methionine and cysteine which is converted from the precursor methionine prevent both fibrosis and liver cell death. However cysteine is a double edged sword. When it is given in excessive doses it will promote liver cell death 5. On the other hand methionine administration allows the body to convert what it needs without leading to cysteine excess and cysteine induced injury. Methionine as a precursor amino acid creates the proper balance.

In Further Observations On The Production And Prevention Of Dietary Hepatic Injury In Rats, Paul Gyorgy, M.D., Alum Harry Goldblatt, M.D, The Journal of Experimental Medicine, Vol 89, 245-268, 1949 the authors concluded that massive or zonal hepatic necrosis (cell death) can be induced by fats with high unsaturated fat content such as lard and cod liver oil and that tocopherol and the sulpher containing amino acids (either methionine or cysteine) can protect against this occurrence. Nine years worth of data led them to believe that fat infiltration in the liver led to cirrhosis of the liver. Without lipotropic factors, or diets devoid of choline, methionine or cysteine fat incursions reached a peak within 21 days with the manifestation of fibrosis occurring 70-100 days later. During this time period cells die from blood flow restriction without much initial indication of problem. The accumulated damage however results in fibrosis.

The fatty incursions specifically lard and cod liver oil promote destruction of tocopherol. If those substances that promote fat flow from the liver are deficient (i.e. methionine and choline) large scale liver cell death occurs. Supplementing with choline and methionine prevents cirrhosis of the liver. Tocopherol as well as cysteine supplementation to some extent also overcame the development of necrosis however cysteine in larger quantities enhanced the production of cirrhosis of the liver.

The liver has a powerful regenerative capacity that can not be overcome when faced with both continued ingestion of certain unsaturated fats which leads to infiltration and deficiencies of methionine, choline and tocopherol. The authors concluded that regular intake of lipotropic factors such as methionine will help prevent the potential for the liver to fail to overcome an assault which will overwhelm its regenerative capacity and result in massive cell death and cirrhosis.

References:

1 – Koteish A, Diehl AM, Animal models of steatohepatitis, Best Pract Res Clin Gastroenterol 16: 679–690, 2002
2 – Shivapurkar N, Poirier LA, Tissue levels of S-adenosylmethionine and S-adenosylhomocysteine in rats fed methyl-deficient, amino acid-defined diets for one to five weeks, Carcinogenesis 4: 1051–1057, 1983
3 – Duce AM, Ortiz P, Cabrero C, Mato JM, S-adenosyl-L-methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis, Hepatology 8: 65–68, 1988
4 – Llovet JM, Burroughs A, Bruix J, Hepatocellular carcinoma, Lancet 362: 1907–1917, 2003
5 – Curtis, A. C.; NewburghThe Toxic Action Of Cystine On The Liver Of The Albino Rat, Arch Intern Med. 1927;39(6):828-832

Conclusion

This article examined the potential contribution to health and wellbeing of each of the ingredients that make up Synthergine™ and found that they may contribute to achieving a balance during times when the liver is under stress.

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Written by: M.M. a/k/a DatBtrue
Copyright 2009 by M.M. a/k/a DatBtrue
Licensed in perpetuity to Synthetek Industries Pty Ltd.
All rights reserved.

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