Elimination of Potential Inhibitors
Eliminating exposure to inhibitor(s) will improve effectiveness. Exposure can come through the workplace, the environment and the home, as well as supplements and dietary sources. These substances can inhibit CYP1B1 function, or cell uptake of Salvestrols. The presence of potential inhibitors is the first thing that needs to be addressed if there is a slow response.
• Fungicide, herbicide and pesticide residues found in conventionally grown foods
Sweeteners & Sugar Substitutes
• Inhibit the ?-glucuronidase enzyme, which is necessary to cleave off transport sugars at the tumour site before Salvestrols enter the cell
• Anything designed as a sugar mimic is a problem; artificial as well as natural sweeteners, stevia etc.
• Naringenin is a potent inhibitor of CYP1B1
• Has similar bioavailability to Salvestrols and competes for CYP1B1 binding site
• Hesperetin from grapefruit also inhibits but to a lesser extent
Excessive Juice Consumption
• Floods liver with high levels of phytochemicals
• Liver does not differentiate between phytochemicals; once functional capacity is reached it will metabolize and remove excess via the aglycone clearance pathway, regardless of nutritional value
• In order to skew the ratio in favour of Salvestrols it is wise to limit juice intake to 3 glasses per day
St. John’s Wort
• Hypericin is a direct inhibitor of CYP1B1
• Standardized extracts are an issue
• Non refined, non-standardized extracts are possibly not strong enough to inhibit, but wise to avoid
• Laetrile, B17 (cyanogenic compounds)
• Affects O2 availability, a crucial reductase for salvestrol activation
• Supplements over 50mg (Red wine is not a problem)
• Potentially a metabolite of resveratrol has the inhibitory effect
• Inhibits the ?-glucuronidase enzyme, which is necessary to cleave off transport sugars at the tumor
site before Salvestrols enter the cell.
• Oil and herb
• All major cannabinoids have been shown to inhibit CYP1B1 EROD enzyme activity: ? 9-
tetrahydrocannabinol (? 9-THC), cannabidiol (CBD), cannabinol (CBN)
• Tobacco etc.
• Carbon monoxide binds irreversibly to central haeme group/active site on CYP1B1
• Especially problematic in lung and blood cancers
* There is no minimal intake limit for Stevia and Salvestrol. Stevia is metabolised by beta-glucoronidase which is vital to cleave the sugar molecule off the Salvestrol complex to liberate the Salvestrol and enable it to enter the target cell. Stevia and other sugar substitutes are competitive inhibitors of beta-glucoronidase which reduces the therapeutic effect of Salvestrol as it cannot enter target cells to bind with CYP1B1 if the sugar molecule has not been cleaved. All sugar substitutes utilise beta-glucoronidase so it is best avoided when taking Salvestrol. I understand this may pose a problem with other supplements as most are using Stevia in their powder preparation. If this is the case, I would recommend dosing any supplements that contain stevia after 3pm when CYP1B1 activity declines and Salvestrol is not taken. (When taking a morning and midday dose of Salvestrols) The half life of ingested Stevia and other sugar substitutes is approximately 3-4 hours.
Q: Are there any interactions between Salvestrol and liquid herbs Nigella sativa and Rabdosia rubescens?
A: There is no negative interactions with Salvestrol. Nigella sativa is a weak inhibitor of CYP3A4 and may inhibit CYP2D6, CYP2C9 or CYP2C19 (or both). Rabdosia rubescens inhibits DNA polymerase and plays a part in the activation of the caspase pathway.
Q: Is there any interaction between Fulvic or Humic acid and Salvestrol?
A: There is no synergistic nor inhibitory effect with Salvestrol. In studies Fulvic and Humic acid have shown anti-inflammatory and antioxidant properties.
Q: Why do some articles imply CYP1B1 exists in healthy cells?
A: This confusion arises in reviews measuring mRNA CYP1B1 which is completely different to measuring CYP1B1 protein or the CYP1B1 enzyme which is over expressed in cancer cells.
Strobilurins and other Fungicides
• Potent inhibitors of CYP1B1
• Used in agriculture, on golf courses, sports fields, public park areas, in new carpeting, house paints,
cleaning agents & air conditioning ductwork
• They are designed to inhibit CYP enzymes
• High bioavailability and high affinity with CYP1B1, therefore very potent inhibitors
• Inhibitory effect at a very low titre
Herbicides & Pesticides
• Inhibit cytochrome P450s
• Used in agriculture, residues can be found on many commercially grown crops
• For example, WHO has recently reclassified status of glyphosate to ‘probable carcinogen’; our scientists suspect that one of the mechanisms of action is to specifically inhibit CYP1B1
Topical Antifungal Agents
• Potent inhibitors of CYP1B1
• For example, Ketoconazole is a known CYP enzyme inhibitor, it is one of many synthetic antifungal
compounds added to various antifungal creams and antidandruff shampoos (Nizoral, Sebizole, Head
& Shoulders, Selsun, ZPII)
• Topical applications can be especially harmful as they are absorbed through the skin and avoid first
Main points relevant to Salvestrol-CYP1B1-DIM
- DIM induces EROD activity of CYP1B1. (Ie. it increases the catalytic activity of CYP1B1, theoretically improving ability to activate Salvestrols.)DIM may also influence CYP19 (aromatase)
- DIM works as a hormonal modulator by increasing the conversion rate of reactive oestrogens (4 & 16 alpha hydroxyestrogens) to less active/estrogenic 2-hydroxyestrogens
- 2-hydroxyestrogens may also act as anti-oestrogens in presence of 17 beta estradiol
- Salvestrols will inhibit conversion of 17 beta estradiol by CYP1B1 to more reactive species, theoretically leaving more 17 beta estradiol present- leading to additional anti-estrogenic effects of 2 hydroxyestrogens
- This would suggest that all oestrogen responsive tumours would benefit from a combination of DIM + Salvestrol
(DIM not to be used during pregnancy or lactation)
The Salvestrols have to be absorbed and be transported to the cancer cells (that is, they have to be bioavailable). They then have to enter the cancer cell and be metabolised by CYP1B1 to produce a metabolite that will initiate apoptosis. As you can see there are a variety of things that all must happen for the desired outcome. When a person is in poor health any of these processes are areas where a failure can occur.
When I hear that someone is having a poor response to Salvestrols my immediate thought is that there may have been some exposure to CYP1B1 inhibitors (inhibitors prevent CYP1B1 from metabolising Salvestrols). Laetrile and supplement high level doses of resveratrol will certainly inhibit CYP1B1 and thereby nullify any beneficial effect of taking Salvestrols. Outside of these inhibitors there are a host of environmental inhibitors of CYP1B1, mainly in the form of fungicides.
One can encounter fungicidal inhibitors of CYP1B1 on farms, golf courses, public gardens and also in a host of products. Paint, carpeting, dandruff shampoo, heating vent cleaners, new cars, chemical treatments for toe nail fungus etc., can all contain fungicides that can inhibit CYP1B1. Herbicides that contain glyphosate are also potent inhibitors of CYP enzymes. Residues can be found on many commercially grown crops, especially Round Up by Monsanto. Another area of concern is carbon monoxide from smoking cigarettes or marijuana. In light of this a systematic look for sources of CYP1B1 inhibition is a very good idea in these situations.
Blood testing services to assist with correct dosing of Salvestrols are in development… stay tuned.
For more information visit https://www.naturopathic-care.com/nutrition/cancer-adjuvant-treatment