Mycotoxins: Ochratoxin A (3/3)
*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.
Ochratoxin A
As discussed in the the second blog article about Ochratoxin A, we learned that OTA has the ability to negatively impact a significant number of pathways related to detoxification, oxidative stress, heme biosynthesis, and iron regulation. In this third and final article about OTA, we introduce various supplements and probiotics that have been shown to counteract the negative impacts of OTA exposure.
“The major detoxification pathways for Ochratoxin A include: Phase 1: CYP1a1, CYP1a2, CYP2c9, CYP3a4; Phase 2 Conjugation: Glucuronidation, Glutathione, Amino Acids, and Acetylation.”
Why Read This Article?
You may find this article interesting if you:
want to learn about which herbs, vitamins, minerals, and other supplements have been shown to combat the negative effects OTA exposure has on antioxidant and metabolic pathways
want to understand which enzymes are involved in the detoxification of OTA and how to support their function
The Antioxidant and Metabolic Impacts of OTA Exposure and How to Counteract Them
While OTA is known to down-regulate important antioxidant enzymes (NrF2 via Keap 1), inhibit the HMOX1 gene, and negatively effect detoxification pathways, there are readily available supplements that have been shown to help counteract these negative impacts.
OTA has been shown to:
Down-regulates the NrF2 enzyme via the Keap1 pathway
Sulfurophane is known to modulate the Keap 1 / NrF2 pathway
Inhibit the HMOX1 gene, which facilitates the storage of iron as ferritin, controls NADPH/NOX/Mast Cell Activation (mast cells are stimulated by elevated iNOS, NADPH Oxidase, and impairment of HMOX1)
Hops upregulates HMOX1
Up-regulate iNOS (POTS), NFKB, and NADPH Oxidase, all of which are NAD-consuming
iNOS is calmed by Andrographis, Oregano, Sage, Resveratrol, Fenugreek
NFKB is calmed by Resveratrol and Hops
NADPH Oxidase is calmed by Blueberry extract, Rosemary, Fisetin, Quercetin,
Cause excess nitrosation (peroxynitrite, damaging free radical)
Hydroxy B12, Rosemary, Witch Hazel, Pycnogenol are peroxynitrite scavengers
Cause lowered amino acid catabolism, potentially impacting cellular processes and resulting in higher levels of some amino acids, lower fatty acid oxidation, higher carnitine, and lowered Alinine
Phenylalanine helps recover the suppressed gene function PHEN
Phenylalinine prevents OTA poisoning in mice.[20]
Lead to mitochondrial dysfunction (membrane potential compromise - phospholipid and cell membrane oxidation)
ER Stress, Super Oxide, and Calpain production have recently become a focus in research related to cell death
Induce calpain activity
Apocynin attenuates this stress.[10] It is also a potent inhibitor of NADPH Oxidase[29]
Lead to metabolic dysfunction (amino acid and fatty acid metabolism effected)
Result in glial cell reactivity, brain inflammation
Lead to induction of Aryl Hydrocarbon Receptor (AHR), leading to NMDA Receptor Activation
AHR is calmed by Rosemary and Milk Thistle (which inhibits Glucuronidation)
Lead to induction of HIF1a - Hypoxia
Astragulus and Rhodiola calm this induction
Cause induction of Ferroptosis (unmitigated cell death), via GPX4 and FXR inhibition, and dysregulation of iron metabolism (i.e., up-regulation of iron importers and down-regulation of iron exporters)
GPX4 is upregulated by Andrographis, Astragulus, and Rosemary
FXR is induced by Reishi and Physlium Husk
Curcumin is a potent iron scavenger
Detoxification of Ochratoxin A
Cytochrome P450 Detoxification Pathways
OTA is detoxified via the following Cytochrome P450 enzymes:
CYP1A1
CYP1A2
CYP2C9
CYP3A4
Dill up-regulates CYP1A2, CYP2C19, NAT2, and SULT1A1 [31]
St. John’s Wort, Valerian, and Ginkgo can support some of these enzymes:
“In addition to induction of CYP3A4 by St. John's Wort, common valerian and Ginkgo biloba increased the activity of CYP3A4 and 2D6 and CYP1A2 and 2D6, respectively. A general inhibitory potential was observed for horse chestnut, Echinacea purpurea and common sage.”[32]
"St. John's wort inhibited CYP3A4 metabolism at the highest applied concentration. Horse chestnut might be a herb with high inhibition potentials in vivo and should be explored further at lower concentrations."[32]
“We show for the first time that G. biloba may exert opposite and biphasic effects on CYP1A2 and CYP2D6 metabolism. Induction of CYP1A2 and inhibition of CYP2D6 were found at low concentrations; the opposite was observed at high concentrations. CYP2D6 activity, regarded generally as non-inducible, was increased by exposure to common valerian (linear to dose) and G. biloba (highest concentration).”[32]
Phase 2 Detoxification
Major Phase 2 detoxification pathways for OTA involve glutathione, amino acid conjugation, and glucuronidation.
Andrographis up-regulates the glutathione gene GSTA1, the gene involved in glutathione detoxification of OTA. [15]
Amino Acid conjugation is supported by Glycine, Glutamine
Glucuronidation is supported by Rosemary, Astaxanthin, Pterostilbene, Calcium D Glucarate, Dandelion, and Ellagic Acid.
Note that Milk Thistle is a potent inhibitor of many glucuronidation genes, and Andrographis has some glucuronidation inhibition properties as well.
Bio-detoxification of OTA by Absorption[15]:
Saccharomyces boulardii/cervaisae
Lactobacillus plantarum LOCK 0862, L. brevis LOCK 0845, and L. sanfranciscensis LOCK 0866 reduced the absorption of OTA, perhaps acting as potential binders
Bacillus lichenformis (in MegaSpore Biotic)
Additional Compounds Shown to Counteract the Negative Impacts of Ochratoxin A
Astaxanthin (ASTA)
Astaxanthin alleviated OTA-induced mitochondrial dynamic imbalance, inhibited mitochondrial division (DRP1, mff), and promoted mitochondrial fusion (OPA1, MFN1, MFN2). In conclusion, ASTA can decrease OTA-induced oxidative damage, thereby alleviating endoplasmic reticulum stress and mitochondrial dynamic imbalance.[16]
Astaxanthin up-regulates NrF2. It also up-regulates PON1, a gene that modulates oxidative stress by scavenging superoxide.
Selenium
Selenium combined with other antioxidants such as CoQ10, L-carnitine, Zn, Mg, N-acetyl cysteine, vitamin C, vitamin E or tamoxifen, to intervene in apoptosis induced by OTA in livers of mice was also investigated. [17]
Selenium is the cofactor for many of the glutathione enzymes (GPX, GST's)
High dose selenium (dose TBD) has been shown to induce ferroptosis - so care must be taken on dosing (generally 100mcg or less).
Curcumin
Curcumin upregulates NrF2, scavenges iron, and regulates TNFA.
“OTA also significantly influenced the metabolism of the intestinal microbiota, such as tryptophan metabolism and glyceropholipid metabolism. Curcumin could alleviate the upregulation of oxidative stress pathways induced by OTA and could alleviate oxidative injury and lipid metabolism disruption by modulating the cecum microbiota.”[18]
Bacillus subtilis
Bacillus subtilis degrades OTA
The degradation of OTA to OTα (7-carboxy-5-chloro-8-hydroxy-3,4-dihydro-3-R-methylisocoumarin) is the most important mechanism of OTA biodegradation - OTα is considered much less toxic than OTA.[15]
Bacillus subtilis CW 14 could degrade 97.6% of OTA (6 μg/mL) within 24 hours. It is a common spore-based probiotic species, and is readily available in Megaspore, Just Thrive, and many other probiotic brands
Melatonin
Melatonin helped to protect rats who were exposed to OTA for 28 days. [22]
Melatonin exhibits a preventive effect against OTA-induced oxidative stress and structural damage in the kidney through its role in the scavenging of free radicals and/or the prevention of lipid peroxidation. Alpha-tocopherol (vitamin E) in the diet decreased by 58% the total DNA adduct provoked in kidney by a single administration of OTA in mouse and rat kidney. Vit C, Artichoke extract and sesame seeds given to laying hens in their diet showed protection against decreased egg production and toxic effect on various organs due to ochratoxin. Vitamins A, C, E with pre-treatment showed reduced number of DNA adducts in kidney by 70%, 90%, 80% for Vitamins A, C, E. [17,26]
Melatonin scavenges hydroxyl radicals and Vit E inhibits lipid peroxidation. The protection offered by artichoke extract and sesame seeds is intriguing.
Selenium
Selenium blocks the increase of DNMT1, DNMT3a and HDAC1 mRNA and protein expression; reversed the decreases of glutathione peroxidase 1 (GPx1) mRNA and protein expression; and promoted the increases of SOCS3 mRNA and protein expression induced by OTA.[27]
Selenium is the cofactor for most of the GPX and GST genes (glutathione peroxidase, and s transferase)
Panax ginseng
GPX1 is up-regulated by Panax ginseng
Lycopene
Lycopene supplementation in the presence of OTA increased GPx1 activity and GSH levels, and decreased apoptotic cell death in both cortex and medulla vs. control.
Lycopene is found in red, pink and orange colored foods, including tomatoes, watermelon, pink grapefruit, asparagus, red cabbage, guava, papaya, red bell pepper, persimmon, and mango.
Lycopene up regulates GSR, which recycles glutathione
Epigallocatechin gallate (EGCG)
EGCG, commonly found in green tea, has been shown to be effective in offering protection from OTA.[28]
EGCG protects GPX4 from being downregulated by blocking the GPX4 inhibition site from RS3.
Note that EGCG is a potent inhibitor of COMT, so consideration of COMT status should be given.
3-O-β-D-glucoside
The cyanidin 3-O-β-D-glucoside (C3G) is a type of anthocyanin found in beans, fruits, vegetables and red wine. It has antioxidant properties that may counteract oxidative damage from OTA.[25]
Antioxidants
Catalase and SOD have protective effect in rats exposed to OTA. [22]
Antioxidant support using the supplements Exogenous Catalase by SuperSmart and SOD Booster by Life Extension may be helpful
NrF2 / Keap1 / NQO1 support may be helpful
Licorice
Licorice extract has been shown to offer a protective effect from OTA exposure in rats. [22]
Licorice down-regulates iNOS / NOS2; NOS2 (can produce the free radical, superoxide)
Licorice can raise blood pressure significantly
Green coffee powder
Green coffee powder protected rats from OTA effects. [24]
Caffeine induces sulfation
N-acetyl Cysteine (NAC)
N-acetyl Cysteine has been shown to bind directly with OTA or metabolites and is removed in the urine
NAC is usually the rate-limiting ingredient in glutathione production
Resveratrol
Resveratrol is a compound found in grapes that controls Aspergillus carbonarius growth and ochratoxin A biosynthesis, and it has also been used in research to attenuate damage from OTA
Resveratrol up-regulates NrF2 / Keap 1 / NQO1, though sulfurophane is much stronger
Milk thistle (Silybum marianim), Ashwaghanda (Withania somnifera), and Gotu kola (Centella asiatica) were all shown to protect young chicks from OTA toxicity.[21]
Interestingly, Milk Thistle down-regulates glucuronidation, so this seems to conflict with other references
The Importance of the SLC7A11 Gene
The SLC7A11 gene plays an important role in glutathione production by using cysteine to create glutathione:
"System Xc- is an important antioxidant system composed of solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2) subunits in the cell membrane, which is essential for the synthesis of glutathione. It can take up extracellular cystine in the cell in a 1:1 ratio and is rapidly reduced to cysteine while pumping out glutamate. Furthermore, a study found that tumor suppressor gene p53 could inhibit the absorption of cystine by System Xc- via down-regulating the expression of SLC7A11, which ultimately triggered ferroptosis. Therefore, GSH, GPX4, and system Xc- are important targets for regulating ferroptosis by medicines"[30]
Fucoidan - Rescues SLC7A11
"Ferroptosis is caused by lipid peroxidation, and Chinese herbal medicine can be used to treat ferroptosis-related diseases. Some researchers showed that fucoidan inhibited iron overload induced by long-term alcohol exposure and protected hepatocytes from ferroptosis. Specifically, fucoidan attenuated alcohol-induced liver oxidative damage in rats by upregulating the p62/Nrf2/SLC7A11 pathway and lowering serum ferritin levels, thereby inhibiting ferroptosis. The environmental pollutant di (2-ethylhexyl) phthalate (DEHP) is a threat to human health. In rats, Dai found that DEHP exposure disrupted iron ion homeostasis, increased lipid peroxidation, and inhibited cysteine/glutamate antiporter, whereas lycopene supplementation dramatically suppressed these ferroptosis characteristics"[30,33]
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