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30.03.2011


Nolvadex works differently

The working mechanism of anti-oestrogen tamoxifen citrate known to chemical athletes as 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 clomid, raloxifene and toremifene.

Tamoxifene


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.

Because a deactivated estradiol receptor means that estradiol no longer has any effect, nolvadex 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 nolvadex 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 nolvadex apparently does function as an oestrogen. The researchers weren't so convinced, so they looked further.

Through genomics technology the researchers identified a second way in which nolvadex works. When they looked at which genes nolvadex 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 nolvadex 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 nolvadex 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.

The research also raises the question whether long-term use of nolvadex is accompanied by side effects that we have hitherto not considered. We now know at least that in cell studies nolvadex has the same effect as dioxins. And they aren't healthy, are they?

Source:
Mol Endocrinol. 2010 Jan; 24(1): 33-46.

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