It’s not unusual for people, especially those with Th1 disease, to find that soy doesn’t always work well in their diet.

But the reason why soy appears to cause problems in many people with Th1 disease remained largely speculative until several month ago, when biomedical researcher Trevor Marshall used molecular modeling software to observe the way that the primary soy isoflavone (or antioxidant), called Genistein, interacts with the Vitamin D Receptor.

Marshall’s model of 1,25-D and Genistein as they dock into the VDR.

His models revealed that Genistein is a partial agonist (activator) of the VDR, and that the substance forms hydrogen bonds with several of the same residues as the vitamin D metabolite 1,25-D (which also activates the VDR).

But, Marshall warned, there’s a catch. Genistein doesn’t have the “tail” of Vitamin D or Benicar, meaning that it cannot transcribe certain genes “which need co-activators requiring helix 12 to be stabilized.”

This suggests that Genistein interferes with the operation of the VDR, as well as with the operation of two other receptors (PPAR-gamma and PPAR-alpha), all of which are key to the immune system.

Huh? If I just lost you on the last few sentences, they boil down to the following: Marshall’s model shows that Genistein binds and activates the VDR. Yet it appears to modulate its activity, and the activity of several nearby receptors, in a way that can dysregulate the activity of the immune system.

But the above conclusion is based on a molecular model. “How much faith can we put into molecular modeling research?” some skeptics might ask.

A study published this week by researchers at Department of Biological Sciences at University of Notre Dame in Indiana suggests that molecular modeling software, when used effectively, can be pretty darn accurate.

In a paper published in the Journal of steroid biochemistry and molecular biology, the team confirmed that Genistein does indeed bind and adjust the activity of the VDR.[1]

The Notre Dame researchers had previously characterized an area in the human VDR gene (called a promoter), that, when bound by certain substances, adjusts the activity of the Vitamin D Receptor. When the team treated this promoter region with Genistein, they found that the substance up-regulated the transcription of proteins produced by the VDR. They verified these results with a second molecular technique called Western blot analysis.

Now that the ability of Genistein to affect the VDR has also been confirmed by a variety of molecular approaches, Marshall’s message that soy intake should be restricted rings louder and clearer then ever. This is particularly true for people with Th1 disease, who are extra sensitive to substances that dysregulate VDR activity. These people also need the receptor to function optimally in order to help the immune system target the Th1 pathogens.

According to Marshall, problems with soy are dose-dependent. Anything up above the cited “20 grams of roasted soybeans,” or 40mg of isoflavones, is likely to be a problem.


  1. Wietzke, Jennifer A, and JoEllen Welsh. 2003. “Phytoestrogen regulation of a Vitamin D3 receptor promoter and 1,25-dihydroxyvitamin D3 actions in human breast cancer cells.” The Journal of steroid biochemistry and molecular biology 84(2-3):149-57. []