The working mechanism of anti-oestrogen tamoxifen citrate – active ingredient of Nolvadex – is more complex than underground manuals would have you believe. Researchers at Duke University discovered this when they did tests on cells. And their findings are probably valid for all SERMs – so also for clomiphene, raloxifene and toremifene.
SERMs have a different chemical structure from that of estradiol or testosterone. Their spatial structure on the other hand is not that different – they are at least capable of interacting with the receptor for estradiol. A tamoxifen molecule can attach itself to the estradiol receptor and disrupt its working. The estradiol receptor and SERM combination does nothing at all.
Tamoxifen works differently
Because a deactivated estradiol receptor means that estradiol no longer has any effect, tamoxifen is an anti-oestrogen, just like the other SERMs.
This is what the manuals say, and the story so far is true. But tamoxifen does something else too, the Duke University researchers discovered. They were puzzled as to how it’s possible that tamoxifen also has oestrogenic effects: it keeps bones strong, prevents the womb from breaking down and keeps arteries flexible.
The conventional explanation for these effects is that in some tissues tamoxifen apparently does function as an oestrogen. The researchers weren’t so convinced, so they looked further.
Aryl hydrocarbon receptor
Through genomics technology the researchers identified a second way in which nolvadex works. When they looked at which genes tamoxifen turned on and off, they noticed that the pattern resembled that of 2,3,7,8-tetrachloordibenzo-p-dioxine. Dioxins interact with the aryl hydrocarbon receptor. That’s why the researchers tested whether tamoxifen not only had an effect on the estradiol receptor but also on the aryl hydrocarbon receptor. And yes, it did.
The aryl hydrocarbon receptor signals toxic substances. When cells get a signal from the aryl hydrocarbon receptor they start to produce more detoxifying enzymes like CYP1A1 and CYP1B1. These enzymes convert estradiol into inactive or less active metabolites.
The figures below show the effect of tamoxifen on SKBR3 breast cancer cells. In the siAHR cells the aryl hydrocarbon receptor [AHR] was switched off using a molecular technique, and the effects of tamoxifen disappeared. 4OHT represents the active metabolite of tamoxifen. BMF is a compound that also attaches to the aryl hydrocarbon receptor. Vehicle = no active substances.
The two figures below show what happened when the researchers deactivated the estradiol receptor in MCF7 cells, using a molecular technique. [siERaC] The researchers also used the technique, but without making any changes in the cell. [Mock] The effect of the tamoxifen remained unchanged.
At present there are anti-oestrogen supplements available on the market containing plant extracts that not only sabotage aromatase, but that also activate the aryl hydrocarbon receptor.
Long term use
The research also raises the question whether long-term use of tamoxifen is accompanied by side effects that we have hitherto not considered. We now know at least that in cell studies tamoxifen has the same effect as dioxins. And dioxins aren’t healthy, are they?
Regulation of Aryl Hydrocarbon Receptor Function by Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs), such as tamoxifen (TAM), have been used extensively for the treatment and prevention of breast cancer and other pathologies associated with aberrant estrogen receptor (ER) signaling. These compounds exhibit cell-selective agonist/antagonist activities as a consequence of their ability to induce different conformational changes in ER, thereby enabling it to recruit functionally distinct transcriptional coregulators. However, the observation that SERMs can also regulate aspects of calcium signaling and apoptosis in an ER-independent manner in some systems suggests that some of the activity of drugs within this class may also arise as a consequence of their ability to interact with targets other than ER. In this study, we demonstrate that 4-hydroxy-TAM (4OHT), an active metabolite of TAM, directly binds to and modulates the transcriptional activity of the aryl hydrocarbon receptor (AHR). Of specific interest was the observation, that in the absence of ER, 4OHT can induce the expression of AHR target genes involved in estradiol metabolism, cellular proliferation, and metastasis in cellular models of breast cancer. The potential role for AHR in SERM pharmacology was further underscored by the ability of 4OHT to suppress osteoclast differentiation in vitro in part through AHR. Cumulatively, these findings provide evidence that it is necessary to reevaluate the relative roles of ER and AHR in manifesting the pharmacological actions and therapeutic efficacy of TAM and other SERMs. 4-hydroxy-Tamoxifen directly binds to and modulates the aryl hydrocarbon receptor in the absence of estrogen receptor, thereby modulating gene expression and suppressing in vivo osteoclastogenesis.