3.1 Potential interactions of main estrogen-like natural products

Tamoxifen is an antagonist of the action of estrogen in the breast and used, among other oncologic indications, in treatment of estrogen receptor positive breast cancer, early and advanced, in pre- and postmenopausal women and in men. It can be prescribed for prevention of breast cancer in women that are at high risk for breast cancer. This drug acts as a weak estrogen in bone tissue but as a strong antagonist of the action of estrogen in the breast, being called a selective estrogen receptor modulator (SERM) and some DHI could occur at this level [8].

Estrogen or antiestrogen bioactivity of some natural products should be avoided to prevent a potential DHI. A precaution must be taken when Caucasian patients ingest for example, isoflavones [9] from Astragalus membranaceus (Fisch.) (astragalus), Cimicifuga ramosa L. (black cohosh)[10], Glycine soja L. (soy) [11], or even from (-)-secoisolariciresinol, a lignin present in Linum usitatissimum L. (flax seeds) [12] and Glycyrrhiza glabra (Licorice root). Various medicinal plants from China are estrogen-like as, for instance, roots of Rehmannia glutinosa L., Paeoniae alba, Angelicae sinensis L. [13]. These compounds have estrogen-like activity and act as endocrine disruptors inducing cell proliferation what is a risk for cancer patients. Data from Asians is different, once polymorphisms produce different metabolites [14].

3.2 Risks associated with the use of inhibitors and/or inducers of CYP isoenzymes and carrying proteins

Tamoxifen is extensively converted to active metabolites in humans by hepatic cytochrome P450 enzymes, being CYP3A4 and CYP2D6 the most relevant in the metabolic process. These metabolites may be responsible for many of the effects of the tamoxifen. Therefore, DHI with Tamoxifen are very important to assure that the main biologically active metabolite is produced in the right plasma concentration, and to prevent a fast elimination too. Since the main active metabolite is made by the action of CYP2D6, drugs that are powerful inhibitors of the enzyme’s activity may reduce the effects of Tamoxifen and thus lead to therapeutic ineffectiveness [2,8]. As CYP3A4 contributes to the bioactivation of tamoxifen, drugs that inhibit the activity will lead to a decrease in the formation of the active metabolites (in both possible metabolic pathways), with consequent therapeutic ineffectiveness [2,15].

From the main concerns in Tamoxifen Summary of Product Characteristics (SmPC) we emphasize “In the literature it has been shown that CYP2D6 poor metabolizers have a lowered plasma level of endoxifen, one of the most important active metabolites of tamoxifen. Concomitant medications that inhibit CYP 2D6 may lead to reduced concentrations of the active metabolite endoxifen. Therefore, potent inhibitors of CYP 2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided during tamoxifen treatment” and it also advertising that “When Tamoxifen Tablets are used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur”... and as “tamoxifen is metabolised by cytochrome P450 3A4, care is required when coadministering with drugs, such as rifampicin, known to induce this enzyme as tamoxifen levels may be reduced. The clinical relevance of this reduction is unknown” [16].

As various Medicinal Plants, some sold as “botanicals” in Food Supplements, can interfere with CYP3A4 and CYP2D6 and cause DHI, but from the literature is not easy getting them directly with tamoxifen. The relevance of the data collected from other drugs and from clinical reports with our patients, will help to highlight some events and contribute in a near future to better to better adjust the treatment, avoiding unpredictable outcomes.

In some countries as our, patients are often harassed to take Aloe vera (L.) Burm. f. prepared in different ways but mainly as syrup made as an alcoholic beverage. The extract include anthraquinones and some were study as cytotoxic but they are also potent laxatives causing various side effects in the patients, including lesions in intestine, that could be favorable to opportunistic infections once chemotherapy has immunosuppressive effect [17]. A few studies were carried out with this cactus and even in a study designed to evaluate in vitro inhibition of these enzymes for ethanolic extract of Aloe vera latex (Aloe barbadensis Miller), it was concluded that there was inhibition of CYP3A4 and CYP2D6 by a double mechanism of inhibition (reversibly and irreversibly), with a decrease in the active metabolites and, thus, therapeutic ineffectiveness [18].

Other potential inhibitors of CYP3A4 are extracts from roots of Curcuma, Ginger, Ginseng and Valerian [19]. It should be adjusted the dose of tamoxifen if the patient insist in the intake, otherwise the bioactivation of Tamoxifen will be compromise.

Caffeic acid and/or its derivatives present in many medicinal plants as Camellia sinensis L. (green and black tea, among others), Cimicifuga racemosa L. (black cohosh), Geranium robertianum L. (herb Robert) [19], Matricaria recutita L. (matricaria), Melissa officinalis L. (balm), Rosmarinus officinalis (rosemary), Salvia officinalis L. (salvia), Verbena officinalis L. (verbena), among others, as in coffee, olive oil, many fruits and vegetables, wine, bee pollen and propolis, making them potential inhibitors of 2C9 and CYP3A4 [20]. From the medicinal plants cited above, in our clinical reports we had DHI with Aloe vera, Geranium and Verbena, that are in line with this hypothesis, reinforcing the potential risk and alerts should be given by the health professionals to the patients about these possible situations. The fact that we do not have notifications of the DHI with other plants cited above does not mean that they cannot occur.

Since the wide variety of plants and food products containing caffeic acid and its derivatives, as well as other compounds, it is important to recommend to the patient for do not change their diet during treatment, because the Tamoxifen dose is adjusted according to the usual diet. Any change in it, as introduction of supplementation, increased coffee intake or infusions, among others) should be reported to the doctor, before taking them, so that the risk can be assessed.

Orange Juice and St. John's Worth, can increase the rate of elimination of drugs by CYP3A4 and P-glycoprotein induction but in the case of Tamoxifen, depending of the extent of the interaction, sometimes the increase of the secondary metabolites could arise to a toxic event. Despite that, in our patients taking high levels of orange juice (3 oranges/ two times a day) as possible detox product the therapeutic failure occurs in concomitance with diarrhea too.

Some of our patients also take medicinal mushrooms. They are mostly used in Asia and nowadays commercialized in Europe for different purposes even for cancer treatments associated to Conventional therapies. Some of the more commonly used species by our patients include Coriolus versicolor (turkey tail), Ganoderma lucidum (reishi), Grifola frondosa (maitake), Lentinus edodes (shiitake), and Poriacocos (Schw.) Wolf. The main raison, as they say, is because in herbal stores, internet and by some Complementary therapists, they are encouraged to take those products to stimulate immune system. Despite a possible beneficial effect, not fully established, DHI should be evaluated and patients follow-up include possible changes in absorption, due to polysaccharides content of mushrooms and CYP interactions although they have not yet been duly clarified.

Considering the cases that have arisen during these 9 years in the OIPM/FFUC and taking into account that clinical outcomes were collected with Caucasian patients, we could infer that the therapeutic ineffectiveness was not due to the genetic polymorphism of CYP2D6, as could be implicit from the discussion did above. Since, by eliminating the inhibitory and / or inducing agents of the enzyme complex in question, the efficacy of tamoxifen therapy has been restored to have plasma concentration values within the range of therapeutic window.

Another issue that is discussed sometimes but in the majority of the threatments is not taken in account, is that Tamoxifen and metabolites endoxifen and 4-hydroxy-tamoxifen exposure could be associated to seasonal variations, with considerable higher plasma concentrations during summer. Recently data concluded, what is already known, that CYP3A4 contributes to the bioactivation of Tamoxifen through formation of 4-hydroxy-tamoxifen and becomes increasingly important in case of reduced or absent CYP2D6 activity. Seasonal variations also influence the plasma concentration levels of the active metabolites, being higher in the summer (there is greater exposure to vitamin D) [21]. It is known that there are nuclear receptors responsible for the induction of metabolizing enzymes, among which we can highlight Pregnane X receptor (PRX) and Vitamin-D-binding

receptor (VDR). PXR is the steroid and xenobiotic receptor and VDR is the vitamin D receptor. These receptors, when active, will lead to a response at the level of genetic transcription since this mechanism aims to detoxify and eliminate the xenobiotic. PXR likewise regulates the expression of CYP3A4 as well as VDR. During the summer, with increased sun exposure, there is more production of vitamin D and this, when it binds to VDR, will induce CYP3A4 (among other enzymes) [22]. In countries as our, with high levels of sun exposure, particular care could be taken since an increase of the metabolization of tamoxifen ultimately increase the concentrations of active metabolites at this time of year.

3.3 Angiogenic potential plants

Angiogenesis is the growth of neovessels from existing vasculature and angiogenic diseases result from new blood vessels growing either excessively, as in cancer, diabetic retinopathy and psoriasis. It is consider a key step in tumor growth, invasion and metastasis [23].

Is not easy to make a statement that help to prevent these potential interactions. The selection of several plants is very difficult to do, since sometimes for the same product they appear with angiogenic and anti-angiogenic activity in literature, as for instance, Aloe vera, Panax ginseng, Vitis spp. (grape). Anyway, from those controversial results, a special information should be given to patients in order to prevent a greater vascularization of the tumor process; in the meantime, we wait for more robust assays associated with angiogenic activity.

Others as Astragalus membranaceus, Angelica sinensis, Rehmannia glutinosa (Jun) and Salvia miltiorrhiza are potential angiogenic plants and the risk associated to the intake is more clear [23,24].

All of them, were unfortunately recommended to some of our patients as co-adjuvants of the treatments, by the players cited above, and the outcomes involved DHI in various clinical reports in addition to a potential vascularization of the tumor in others. As an example occurred in one of our clinical reports involving the intake of Panax ginseng in a Caucasian patient, 58 years old, with a meningioma in the sellar region medicated with Tamoxifen. The drug was ineffective because Ginseng inhibits CYP3A4 and CYP2D6 and also contributes to the increase angiogenesis. Briefly, in the first surgery, an increased vascularization was verified and the procedure had to be suspended. Following the suspension of the plant, a decrease in vascularization was observed in the following surgical process, as well as a recession of the meningioma, which allowed a safe removal.