This article is not medical advice. Before starting any health related regimen, seek the advice of your Primary Care Physician or an M.D.
This article summarizes some of the effects by Ochratoxin A prevalent in the existing literature, and then lists potential ways to mitigate these effects that exist in the literature as well. There are a number of factors listed below that point to benefits from anti oxidants themselves (e.g. Vit E) as well as supporting the body's natural antioxidant systems. Understanding your nutritional status of various anti oxidants and your genetic status for various anti oxidant genes may be something to consider. Lastly, a number of probiotics show absorption capability of OTA and others show biotransformation ability. One potential way to focus and narrow the scope of things to consider is to see where nutritional and genetic weakness exists most profoundly, and to start there in terms of supports.
OTA down regulates important anti oxidant enzymes NrF2, through Keap 1
Sulfurophane modulates the Keap 1 / NrF2 pathway
Inhibits HMOX1 - stores iron into ferritin, controls NADPH/NOX/Mast Cell Activation
Hops upregulates HMOX1
Upregulates iNOS (POTS), NFKB, and NADPH Oxidase, all 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,
Excess nitrosation - peroxynitrite, damaging free radical
Hydroxy B12, Rosemary, Witch Hazel, Pycnogenol are peroxynitrite scavengers
Lowered amino acid catabolism - higher amino levels, lower fatty acid oxidation, higher carnitine, and lowered Alinine
Phenylainine helps recover the suppressed gene function PHEN
Mitochondrial Dysfunction (membrane potential compromise - phospholipid and cell membrane oxidations)
ER Stress, Super Oxide, and Calpain production have recently become a focus in research related to cell death.
OTA induces calpain activity, and apocynin attenuates this stress.[10] It is also a potent inhibitor of NADPH Oxidase[29].
Metabolic dysfunction (amino acid and fatty acid metabolism effected)
Glial cell reactivity, brain inflammation
Mast cells are stimulated by elevated iNOS, NADPH Oxidase, and impairment of HMOX1
Induction of Aryl Hydrocarbon Receptor - AHR - NMDA Receptor Activation
AHR is calmed by Rosemary and Milk Thistle (which inhibits Glucuronidation)
Induction of HIF1a - Hypoxia
Which can be calmed by Astragulus and Rhodiola
Induction of Ferroptosis (unmitigated cell death) via GPX4 and FXR Inhibition and Iron Dysregulation - upregulation 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
Circumin is a potent iron scavenger
Major CYP 450 Phase 1 Pathways for Ochratoxin A:
CYP1A1
CYP1A2
CYP2C9
CYP3A4
Dill upregulates CYP1A2, CYP2C19, NAT2, and SULT1A1 [31]
"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]
Major Phase 2 detoxification pathways for OTA (Glutathione, Amino Acid, Glucuronidation)
Uses the glutathione gene GSTA1 for glutathione detoxification. [15]
Glutathione gene GSTA1 used by OTA is upregulated by Andrographis (inhibits glucuronidation somewhat)
Amino Acid conjugated is supported by Glycine, Glutamine
Glucuronidation is supported by Rosemary, Astaxanthin, Pterostilbene, Calcium D Glucorate, Dandelion, and Ellagic Acid. Milk Thistle is potent inhibitor of many glucuronidation genes, and Andrographis has some glucuronidation inhibition properties as well.
Biotdetoxification of OTA by Absorption[15]:
Sacromyces Boulardii/Cervaisae
Lactobacillus plantarum LOCK 0862, L. brevis LOCK 0845, and L. sanfranciscensis LOCK 0866 reduced the absorption of OTA - perhaps potential binders
bacillus lichenformis (in MegaSpore Biotic)
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 upregulates NrF2, and PON1 which is a Super Oxide scavenging gene.
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).
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]
Circumin also upregulates NrF2, scavenges iron, and regulates TNFA.
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. Bacillus subtilis degrades OTA. [15]
Bacillus subtilis CW 14 could degrade 97.6% of OTA (6 μg/mL) within 24 h, and is a common spore based probiotic species found in Megaspore, Just Thrive, and many others.
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, Vit E helps lipid peroxidation, artichoke and sesame are interesting
Selenium blocks the increases 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 transferese).
GPX1 is upregulated by Panax Gensing
Lycopene supplementation with 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. Green Tea (EGCG) has also been shown to be effective in offering protection from OTA.[28]
Lycopene up regulates GSR, which recycles glutathione
EGCG protects GPX4 from being downregulated, by blocking the GPX4 inhibition site from RS3. EGCG is a potent inhibitor of COMT, so consideration of COMT status should be given.
The cyanidin 3-O-β-D-glucoside (C3G), an anthocyanin with anti oxidant effects found in beans, fruits, vegetables and red wine, might counteract oxidative damage from OTA.[25]
Consistent with Catalase, GPX4, SOD - anti oxidant support may be helpful.
Licorice extract showed a protective effects from OTA in rats. [22]
Licorice downregulates iNOS / NOS2; NOS2 can produce super oxide (a free radical)
Licorice can raise blood pressure significsntly.
Melatonin helped to protect rats who were exposed to OTA for 28 days. [22]
Green coffee powder protected rats from OTA effects. [24]
Caffeine induces sulfation
Catalase and SOD have protective effect in rats exposed to OTA. [22]
Exogenous Catalase (SuperSmart), SOD Booster By Life Extension, NrF2 / Keap1 / NQO1 support all helpful too.
N-acetyl Cysteine has been shown to combine directly with OTA or metabolites and is removed in the urine.
NAC is usually the rate limiting ingredient in glutathione production.
Resveratrol is used by grapes to control Aspergillus carbonarius growth and ochratoxin A biosynthesis, and has also been used in research to attenuate damage from OTA.
Resveratrol upregulates NrF2 / Keap 1 / NQO1, Sulfurophane much stronger.
Phenylalinine prevents poisoning in mice from OTA.[20]
Three herbs, Silybum marianim - Milk thistle, Withania somnifera - Ashwaghanda, and Centella asiatica - Gotu kola were all shown to protect young chicks from OTA toxicity.[21]
Interestingly Milk Thistle downregulates glucuronidation, so this one has conflicting information.
SLC7A11 - Important for 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]
References:
Ochratoxin A-mediated DNA and protein damage: roles of nitrosative and oxidative stresses
Peroxynitrite scavenger reference
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