Milk Thistle
MILK THISTLE and IRON ISSUES
In a 2008 study, researchers found that the lecithin/silymarin combination decreased circulating blood levels of iron, which indicates that it does have chelating activity. Chelating agents are non-selective. They change iron, as they would change a hazardous heavy metal like lead or mercury. Anemic people are warned against using chelating agents on a regular basis for that reason, unless they also take an iron supplement.
http://www.disabled-world.com/artman/publish/article_664.shtml
Hemochromatosis Diet
When the diagnosis of hemochromatosis is made it is important to adjust the diet so that too much iron is not being absorbed because of an improper diet. The biggest considerations are not to take medications which contain iron, consume too much alcohol or Vitamin C.
Vitamin C enhances the absorption of iron and has been known to precipitate heart palpitations in those with hemochromatosis.
Excessive alcohol consumption which has shown to greatly increase iron absorption in those with hemochromatosis is set at 60g a day. Thus it is important to stay well below this level. The limit should be 30g a day. When a patient has two copies of C282Y and drinks excessive alcohol there is a multiplying affect � not an additive affect � on the absorption of iron. It is deadly to drink too much alcohol if you have hemochromatosis.
The ingestion of black tea has been shown to decrease the absorption of iron. African tea which is becoming popular may contain iron so too much should not be consumed.
Don�t take milk thistle which has often been touted as good for the liver. It can cause severe problems in those with hemochromatosis.
Don�t eat raw shellfish. They may be contaminated with Vibrio vulnificans which thrives in an iron rich environment. There have been fatalities in the northern hemisphere. Cooking inactivates this organism.
Vitamin E � as an antioxidant may be of some help because too much iron may act as an oxidant. However it is probably important not to exceed 400 to 800 IU a day of Vitamin E.
Patients with hemochromatosis should not take supplements unless there are documented deficiencies. There is evidence that those with hemochromatosis may also have an increased ability to absorb other heavy metals. While iron may be removed by bleeding it is very difficult to remove other excess heavy metals.
http://www.nutritionalwellness.com/archives/2010/may/05_bone.php
Iron Chelation
It has also been discovered that milk thistle has an activity toward iron in the body. A few years ago, a group of scientists found that silybin, one of the plant chemicals found in milk thistle and the silymarin extract, had a strong chelating capacity for iron.4 The authors suggested that the herb could be used for iron overload disorders and high ferritin levels (an indicator of iron stores). The toxicity of the silymarin is low compared to the iron-binding drugs.
Since then, I have seen good results in using silymarin at 200 mg three times a day to reduce elevated ferritin or help control the genetic iron overload disorder hemochromatosis. It is good to see this hunch confirmed in a clinical trial. In an open-label trial design, silybin (complexed with phosphatidylcholine [lecithin] to help its bioavailability) significantly reduced serum ferritin by around 15 percent over four weeks in patients with chronic hepatitis C.5 There was no significant change in serum iron or transferrin saturation. However, given this capacity of the actives in milk thistle to bind iron, it is best taken away from meals and iron supplements if iron status is low.
http://www.liverdisease.com/milkthistle_hepatitis.html
Milk thistle (also known as silymarin and its scientific name Silybum marianum) is a tall plant, characterized by sharp spines that resemble artichokes and leaves that are riddled with distinctive white veins. It was originally discovered growing in the Kashmir region bordering India and Pakistan. It can now be found all over the temperate world, growing in dry and rocky soil. Its stems and leaves secrete a milky substance when crushed. The following sections contain important information regarding this popular herb. It is important to be aware that some preparations of milk thistle may contain iron therefore milk thistle should be avoided by people with liver diseases associated with iron overload such as hemochromatosis and some cases of chronic hepatitis C.
http://www.nature.com/ejcn/journal/vaop/ncurrent/abs/ejcn2010136a.html
Milk thistle contains silybin, which is a potential iron chelator. We aimed to determine whether silybin reduced iron absorption in patients with hereditary haemochromatosis. In this crossover study, on three separate occasions, 10 patients who were homozygous for the C282Y mutation in the HFE gene (and fully treated) consumed a vegetarian meal containing 13.9 mg iron with: 200 ml water; 200 ml water and 140 mg silybin (Legalon Forte); or 200 ml tea. Blood was drawn once before, then 0.5, 1, 2, 3 and 4 h after the meal. Consumption of silybin with a meal resulted in a reduction in the postprandial increase in serum iron (AUC±s.e.) compared with water (silybin 1726.6±346.8 versus water 2988.8±167; P<0.05) and tea (silybin 1726.6±346.8 versus tea 2099.3±223.3; P<0.05). In conclusion, silybin has the potential to reduce iron absorption, and this deserves further investigation, as silybin could be an adjunct in the treatment of haemochromatosis.
http://www.cfp.ca/cgi/content/full/53/10/1671
Milk thistle (Silybum marianum) is an herbal product commonly employed in treatment of liver conditions. In this case, milk thistle might have been responsible for exacerbating the clinical and biochemical presentation of C282Y homozygous hemochromatosis. Ceasing to ingest the milk thistle and removing only 2 g of iron by phlebotomy virtually normalized results of liver function tests and iron studies and eliminated this patient’s clinical symptoms. Patients who have C282Y hemochromatosis should be cautious about taking milk thistle.
Milk thistle is held to be a treatment for liver disease, but this is controversial, and hepatotoxicity is possible.1,2 No herbal medications have proven efficacy for treatment of C282Y homozygous hemochromatosis.
- The patient in this case was ingesting 1 pill a day (200 mg) of the Health Balance brand of milk thistle. Milk thistle, an herbal product, is held to be a treatment for liver disease, but this is controversial, and hepatotoxicity is a possibility.
- Based on hemochromatosis gene testing and assessment of her ferritin level and transferrin saturation, this patient was diagnosed with hemochromatosis.
- Ceasing to ingest the milk thistle and removing only 2 g of iron by phlebotomy virtually normalized results of her liver function tests and iron studies and eliminated her clinical symptoms.
SUN CHLORELLA and IRON ISSUES
http://www.nuconceptsinc.com/sun_chlorella.htm
Please Note: Chlorella has great health benefits, however while Chlorella is effective in removing the heavy metal mercury, chlorella will not remove or decrease excess iron levels. Although iron is an essential and important nutrient, excessive levels can cause significant harm. Research has demonstrated a relationship between elevated iron and a number of diseases, including atherosclerosis, heart disease and type-2 diabetes.
Iron appears to be a catalyst in the formation of dangerous free radicals - it is really an "anti-antioxidant", the exact opposite of an antioxidant. Chlorella contains iron and will actually raise iron levels. Men tend to have higher iron stores than women.
Men tend to have more elevated iron levels than women. Pre-menopausal women are less likely to have iron overload since they lose iron each month during menstruation cycles. However, postmenopausal women also tend to accumulate iron.
Measuring your iron levels is an important tool in maintaining optimal health anyway; however, I particularly recommend that men and post-menopausal women have their iron levels checked prior to using chlorella (or other iron-containing supplements). The best way to do this is through a measure of serum ferritin level in conjunction with total iron binding level.
Caution: About 30% of people can't tolerate chlorella. This may be due to optimized function of the enzyme cellulase. If you are unable to tolerate this it would be wise to consider adding an enzyme with cellulase in it to help with digestion of chlorella.
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VITAMIN C and IRON ISSUES
http://en.wikipedia.org/wiki/Vitamin_C
As vitamin C enhances iron absorption,[130] iron poisoning can become an issue to people with rare iron overload disorders, such as haemochromatosis. A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD) can cause sufferers to develop hemolytic anemia after ingesting specific oxidizing substances, such as very large dosages of vitamin C.[131]
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GILBERT'S SYNDROME
http://en.wikipedia.org/wiki/Gilbert's_syndrome
Gilbert's syndrome is caused by a 70%-80% reduction in the glucuronidation activity of the enzyme Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UDP-glucuronosyltransferase 1A1).[18][19]
The enzyme is produced from a gene named UGT1A1, located on human chromosome 2.[20] A normal UGT1A1 gene has a promoter region TATA box containing the genetic subsequence A(TA6)TAA. The allele polymorphism is referred to as UGT1A1*28.
Gilbert's syndrome is most commonly associated with homozygous A(TA7)TAA alleles.[21] In 94% of GS cases, mutations in two of the other glucoronyltransferase variations UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective) are also present. Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as a minor inborn error of metabolism
It has been reported that GS may contribute to an accelerated onset of neonatal jaundice, especially in the presence of increasedhemolysis due to diseases like G6PD deficiency.[
The enzymes that are defective in GS (UGT1A1) are also responsible for some of the liver's ability to detoxify certain drugs
While paracetamol (acetaminophen or brand names Panadol, Tylenol) is not metabolized by UGT1A1,[6] it is metabolized by one of the other enzymes also deficient in some people with GS.[7][8] A subset of people with GS may have an increased risk of paracetamol toxicity.[
http://en.wikipedia.org/wiki/Paracetamol
- Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.[44]
- Sulfation (sulfate conjugation) may account for 20–40%.[44]
MILK THISTLE and GILBERT's SYNDROME
http://dmd.aspetjournals.org/content/28/11/1270.full
Treatment with silymarin (0.1 and 0.25 mM) significantly reduced the activity of CYP3A4 enzyme (by 50 and 100%, respectively) as determined by the formation of 6-β-hydroxy testosterone and the activity of uridine diphosphoglucuronosyl transferase (UGT1A6/9) (by 65 and 100%, respectively) as measured by the formation of 4-methylumbelliferone glucuronide. Silymarin (0.5 mM) also significantly decreased mitochondrial respiration as determined by MTT reduction in human hepatocytes. These observations point to the potential of silymarin to impair hepatic metabolism of certain coadministered drugs in humans. Indiscriminate use of herbal products may lead to altered pharmacokinetics of certain drugs and may result in increased toxicity of certain drugs.
Silymarin has been reported to inhibit certain hepatic enzymes such as aminopyrine demethylase, benzopyrene hydroxylase, hexobarbital hydroxylase, and ethoxy coumarin O-deethylase in rats (Letteron et al., 1990). Silybin is primarily conjugated and excreted in the bile and urine in rats (Lorenz, 1982). Silymarin is known to deplete the pool of uridine diphosphoglucuronic acid (UDPGA)1 in hepatocytes and decrease glucuronidation of bilirubin in rats (Chrungoo et al., 1997b). The above observations would suggest that there would be a competition between silymarin and other drugs that are metabolized by various cytochrome P450 (CYP) enzymes or conjugated to a glucuronide in the liver. Our objective was to evaluate the effect of acute and chronic exposure of silymarin on the activity of CYP3A4 and uridinediphosphoglucuronosyl transferase (UGT1A6/9) in primary cultures of human hepatocytes.
Silymarin, the major component of milk thistle, is reported to inhibit nitric oxide production (Dehmlow et al., 1996), is a potent free radical scavenger and prevents lipid peroxidation (Valenzuela et al., 1985; Muriel and Mourelle, 1990), enhances the activity of hepatocyte RNA polymerase (Sonnenbichler et al., 1976), and complexes toxic free iron (Pietrangelo et al., 1995).
Silymarin has been hypothesized to inhibit the activity of several CYP enzymes in rats. Silymarin has been reported to decrease bilirubin conjugation in patients with liver cirrhosis (Salmi and Sarna, 1982). Based on studies in rats, it has been hypothesized to impair glucuronidation (Chrungoo et al., 1997b)
Figure 1 illustrates the activity of CYP3A4 in the hepatocytes as measured by the formation of 6-β(OH) testosterone in untreated or chronic silymarin treated (0.1 or 0.25 mM) cultures. The formation rate of 6-β(OH) testosterone in the untreated cells was 0.04 nmol/min/mg of protein. Silymarin at both concentrations significantly decreased CYP3A4 activity. Figure2A illustrates the activity of UGT as measured by the formation of 4-MUG after acute treatment (1 h) of silymarin.
The rate of formation of 4-MUG was 0.35 nmol/min/mg of protein in untreated cells. Phenobarbital marginally (less than 2-fold) increased the activity of UGT1A6/9, while silymarin drastically reduced the activity of UGT in these hepatocytes. Figure 2B illustrates the activity of UGT after chronic treatment (for 48 h) of the hepatocytes with silymarin. Chronic treatment with silymarin significantly reduced the activity of UGT1A6/9 at 0.1 mM and completely inhibited the formation of 4-MUG at 0.25 and 0.5 nM.
Our studies clearly document the potential of silymarin to inhibit the metabolism of substrates of CYP3A4 and UGT1A6/9 in humans.CYP3A enzymes are responsible for the metabolism of several drugs. UGT is the primary phase 2 enzyme responsible for the metabolism of several drugs.
The exact reason(s) for the reduced activity of CYP3A4 in silymarin-treated cells is not clear at this time. Depletion of UDPGA and competition for the UGT may be the mechanisms involved in the reduction in UGT activity in presence of silymarin as measured in this study. The observation that UGT1A6/9 activity is lower after acute and chronic silymarin treatment would suggest that down-regulation of UGT1A6/9 is not likely a major mechanism involved.
Additional ongoing studies will address the mechanistic basis for the observations presented here. Our study indicates that the use of silymarin with other drugs that are conjugated by UGT1A6/9 will lead to a reduction in the clearance of certain drugs. In addition, there is also a potential for increased toxicity due to increased formation of toxic metabolite(s) of coadministered drugs in the presence of silymarin. The toxicity of acetaminophen is increased in the presence of drugs that are also conjugated (Kostrubsky 1997).
http://dmd.aspetjournals.org/content/32/6/587.full
Silybin was a potent inhibitor of UGT1A1 and was 14- and 20-fold more selective for UGT1A1 than for UGT1A9 and UGT1A6, respectively. Thus, careful administration of silybin with drugs primarily cleared by P450s 3A4 or 2C9 is advised, since drug-drug interactions cannot be excluded. The clinical significance of in vitro UGT1A1 inhibition is unknown.
The importance of phase I biotransformation, mainly facilitated by cytochromes P450, in the oxidative metabolism and eventual detoxification of drugs and xenobiotics is well recognized (Guengerich, 1991).
Importantly, glucuronidation facilitated by UDP-glucuronosyltransferases (UGTs) is increasingly recognized as a major phase II detoxification pathway in humans (Fisher et al., 2001), and silybin may exert effects on both phase I and phase II metabolic reactions. For instance, silybin has been shown to noncompetitively inhibit denitronifedipine oxidation, mediated by P450 3A4 (Ki = 11 μM), in human liver microsomes (Beckmann-Knopp et al., 2000).
A recent report has, however, indicated that silybin is a potent inhibitor of β-naphthoflavone (P450 1A; IC50 = 0.9 μM) metabolism in cultured hepatoma cells (Gerhauser et al., 2003). Treatment of human hepatocytes with 0.25 mM silymarin inhibited the P450 3A4 activity as measured by the formation of testosterone 6β-hydroxylation (Venkataramanan et al., 2000).
In addition, acute and chronic treatment of hepatocytes with silymarin significantly inhibited glucuronidation of 4-methylumbelliferone (UGT1A6/9) (Venkataramanan et al., 2000). One study in humans demonstrates that silymarin administration decreased the excretion of bilirubin glucuronide in patients with liver cirrhosis due to alcohol abuse (Salmi and Sarna, 1982), although clinical significance was not clearly indicated and other reports on clinical hyperbilirubinemia or interactions between silybin and drugs are lacking.
It is also of interest to determine whether the inhibition of the major hepatic P450s also involves irreversible enzyme inactivation and whether there is evidence for the in vitro inhibition of major hepatic UGTs. The aim of this report was to further investigate the effects of silybin on key human phase I and phase II metabolic enzymes.
Silybin was evaluated for its ability to inactivate human P450s 3A4 and 2C9 using purified recombinant enzymes in a reconstituted system. The inhibition of relevant human hepatic UGTs was also investigated in recombinant cDNA-expressed enzyme preparations.
Irreversibility of the Inactivation of P450 3A4 and 2C9 by Silybin.Table 3 shows the activities of noninactivated and silybin-inactivated P450 3A4 or 2C9 samples following dialysis at 4°C to remove free or reversibly bound silybin. Extensive dialysis failed to restore the activity of the silybin-inactivated samples to levels seen in the control samples.
Addition of fresh reductase back to the inactivated samples also did not result in a major recovery in the P450 3A4 and 2C9 activities. Since silybin is a rather hydrophobic molecule, dialysis may not have completely removed all free or loosely bound inactivator. Therefore, spin column gel filtration was used as well.
With this method, the activity of the inactivated samples also could not be regained after passing the samples through a G-50 gel filtration spin column (data not shown). These results suggest that the inactivation of P450s 3A4 and 2C9 is primarily due to covalent modification of the P450s and that it is irreversible under these conditions and is not due to modification of the NADPH-reductase.
Addition of glutathione (2.5 mM) during the inactivation reaction did not prevent or decrease the loss in activity, suggesting that the silybin reactive intermediate did not leave the active site to react with external residues on the P450s or with reductase (data not shown).
Interestingly, silybin inhibited all of the major hepatic UGTs examined, with IC50 values below 100 μM. Silybin was more selective at inhibiting UGT1A enzymes compared with UGT2B isozymes and was shown to be a very potent inhibitor of UGT1A1 with an IC50 of approximately 1 μM. Silybin was approximately 14- and 20-fold more selective at inhibiting UGT1A1, compared with UGTs 1A9 and 1A6, respectively.
Flavonoids are present ubiquitously in plants and are consumed when vegetables, fruits, and beverages such as tea and red wine are ingested (Hertog et al., 1993). Flavonoids have been shown to play a prominent role in cancer prevention (Bravo, 1998) and to reduce the risk of cardiovascular diseases (Dwyer, 1995). Inhibition of P450 3A4 by flavonoids has been shown (Fuhr, 1998).
Silybin, a major flavonoid constituent of milk thistle extract silybin is a mechanism-based inactivator for P450s 3A4 and 2C9 according to the following observations: 1) inactivation reactions were time-, concentration-, and NADPH-dependent; 2) loss in activity was pseudofirst-order; and 3) loss in enzyme activity was irreversible after extensive dialysis suggesting that the metabolism of silybin resulted in the formation of a reactive intermediate that bound to the 3A4 heme moiety.
Further evidence for a loss in heme was observed using the pyridine hemochrome method, where the percentage loss in the pyridine hemochrome again correlated with the heme loss seen with the HPLC assay or the reduced CO spectrum. It was, therefore, not surprising to find no recovery in the enzymatic activity when silybin-inactivated P450 3A4 or 2C9 samples were extensively dialyzed. Addition of fresh reductase to the dialyzed control and inactivated samples also did not restore enzymatic activity.
Similarly, no metabolism-dependent increase or decrease in the enzymatic activities of P450s 2B6 and 2D6 was seen when these enzymes were incubated with silybin in a reconstituted system (data not shown). A report by Beckmann-Knopp et al. (2000) showed that silybin inhibits seven important human hepatic P450s, of which P450s 3A4 and 2C9 are inhibited more potently.
We have shown that silybin is a mechanismbased inactivator of both P450 3A4 and 2C9 and that this interaction could lead to irreversible enzyme degradation. The inhibition of P450 3A4 by silybin involves several mechanisms again indicating that although inhibition may appear to be competitive, this mechanism also involves destruction of enzyme we have demonstrated the ability of silybin to inhibit the glucuronidation of HFC mediated by a number of important hepatic UGTs.
Interestingly, silybin is a very potent and selective inhibitor of UGT1A1 (IC50 = 1.4 μM). Although UGT1A6 and UGT1A9 were also inhibited, silybin was 14-to 20-fold more selective for UGT1A1. The in vivo significance of this phenomenon could be important but is presently unknown, since there are no published reports indicating a clinical interaction with bilirubin or glucuronidation of UGT1A1 substrates. UGT1A1 is the sole enzyme responsible for the glucuronidation of bilirubin and contributes to the glucuronidation of several drugs including estradiol, irinotecan, buprenorphine, and naltrexone (Liston et al., 2001)
It is therefore possible that the reduced excretion of bilirubin glucuronide previously observed in alcoholics with liver cirrhosis (Salmi and Sarna, 1982) could be related to inhibition of hepatic UGT1A1 by silybin. It was recently reported that the glucuronidation of SN-38, the active metabolite of the anticancer drug irinotecan, is mainly mediated by UGT1A1 and that patients with Gilbert's disease who have a common genetic polymorphism for UGT1A1 are more likely to present with adverse effects of irinotecan (Iyer et al., 1999).
The IC50 of silybin for UGT1A1 approximates plasma levels, and because biliary levels are much higher, an interaction of silybin with bilirubin or UGT1A1 substrates might be possible. The finding that silybin is also a modestly potent inhibitor of UGT1A6 and 1A9 is in agreement with previous findings in hepatocytes (Venkataramanan et al., 2000), and interactions with compounds that are glucuronidated by these isozymes are not excluded, although based on in vitro findings, an interaction with UGT1A1 substrates would be more likely, if at all.
In conclusion, our results demonstrate that silybin inhibits both phase I and phase II enzymes. This is particularly important because milk thistle is widely available as a herbal supplement or prescription drug and the principal agent in the milk thistle extract inactivates P450s 3A4 and 2C9. Silybin, furthermore, is a potent in vitro inhibitor of UGT1A1. It is therefore advised that care should be taken when milk thistle is used.
Physicians should take special note of all coad-ministered supplements/medications to appropriately monitor therapeutic drug plasma levels or adverse events when prescribing agents primarily cleared by P450s 3A4 and 2C9, or UGT1A1, especially in the absence of clinically relevant information. Carefully controlled clinical studies are needed to define the clinical relevance, if any, of this finding.
http://clincancerres.aacrjournals.org/content/11/21/7800.abstract
Milk thistle (Silybum marianum) is one of the most commonly used herbal therapies, and its principal constituent silybin significantly inhibits cytochrome P450 isoform 3A4 (CYP3A4) and UDP glucuronosyltransferase isoform 1A1 (UGT1A1) in vitro.
http://en.wikipedia.org/wiki/Glucuronosyltransferase
Arguably, the most important of the Phase II (conjugative) enzymes, UGTs have been the subject of increasing scientific enquiry since the mid-to-late 1990s.
The reaction catalyzed by the UGT enzyme involves the addition of a glucuronic acid moiety to xenobiotics and is the most important pathway for the human body's elimination of the top 200 drugs. It is also the major pathway for foreign chemical (dietary, environmental, pharmaceutical) removal for most drugs, dietary substances, toxins and endogenous substances
A deficiency in the bilirubin specific form of glucuronosyltransferase is thought to be the cause of Gilbert's syndrome, which is characterized by hyperbilirubinemia.
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Last Updated- April 2019
Lucy Barnes