New research reveals how certain drugs can induce hidden vitamin B1 deficiencies

NEW YORK, October 20: Vitamin B1, also known as thiamine, is crucial for cell survival; however, the human body is unable to produce it. To maintain optimal levels, it is important to include foods such as salmon, legumes and brown rice in your diet. Ensuring sufficient intake of vitamin B1 is essential, as a deficiency can lead to serious cardiovascular and nervous system problems, disability or even death.

In some cases, vitamin B1 deficiency can occur in the brain and other vital organs due to the side effects of certain medications. This can happen even when blood levels of B1 are normal, often leading to deficiencies that go undetected until they become severe.

To uncover the reasons for these hidden deficiencies, the Löw group at EMBL Hamburg, in collaboration with the CSSB and the VIB-VUB Center for Structural Biology, used structural biology and biophysical techniques to explore how the vitamin is transported B1 inside the body and what factors. can prevent their movement.

As vitamin B1 travels from the gut to the body’s cells, it must navigate several barriers, starting with the intestinal wall, followed by blood vessels, organs, and finally cell membranes individual The most important barrier is the blood-brain barrier, which protects the brain from toxins in the bloodstream, but also restricts the passage of essential nutrients such as vitamins.

To facilitate the transfer of vitamins and nutrients across these membranes, there are specialized carrier molecules. For vitamin B1, this task is mainly performed by two transporters: SLC19A2 and SLC19A3. Although their importance to human health is recognized, the exact molecular mechanisms behind their function have been unclear.

To elucidate this, the Löw group focused on SLC19A3, a transporter vital for the passage of B1 across the intestinal wall and the blood-brain barrier, both critical phases in the vitamin’s journey.

To observe the transporter in action, the researchers created a “molecular movie” by compiling a series of images obtained using cryo-electron microscopy (cryo-EM).

“With this approach, we captured the dynamics of the transport process and visualized molecular details of how the transporter recognizes and moves the B1 molecule across the cell membrane,” said Christian Löw, group leader and corresponding author of the study

These molecular images allowed the scientists to identify which sections of the SLC19A3 transporter are crucial for its proper functioning. The malfunctioning of these areas can hinder the effectiveness of the carrier. This is important because mutations in these critical regions disrupt B1 transport in the brain, leading to severe neurological symptoms. These rare disorders typically manifest in childhood and are treated with high doses of B1 and other compounds; however, one in 20 patients may die, and nearly a third continue to experience symptoms.

To investigate further, the researchers created a version of the SLC19A3 transporter that carried a mutation responsible for a serious brain disorder known as BTBGD. This model allows them to observe how the mutation alters the transporter’s molecular structure and reduces its ability to bind to B1. Understanding this mechanism may pave the way for developing more effective treatments for BTBGD in the future.

In addition to rare genetic mutations, certain medications can also cause severe symptoms of B1 deficiency. Several commonly prescribed drugs, including some antidepressants, antibiotics, and cancer treatments, have been found to impair SLC19A3 function. This deterioration can cause dangerous deficiencies in B1, affecting the whole body or specific organs.

Brain-related deficiencies are of particular concern because they can arise even with normal blood levels of B1, making them undetectable by standard blood tests. These hidden impairments can silently lead to serious and potentially life-threatening brain dysfunction.

“Although drugs that can induce hidden B1 deficiencies are already known, there are still many to be identified,” said Florian Gabriel, PhD student at EMBL Hamburg and first author of the study. “Finding these drugs is not simple, so our research aimed to simplify this process. We discovered the molecular basis of how certain drug molecules block the SLC19A3 transporter and we are currently using this knowledge to screen all FDA-approved drugs and ‘EMA for similar interactions’.

The Löw group also identified specific structural features that increase the likelihood that a drug will interfere with B1 transport. Using cryo-EM and biophysical techniques, they analyzed how known blockers interact with SLC19A3.

This research has led to the identification of seven new drugs that block the B1 transporter in vitro, which are likely to do so in the human body as well. These include several antidepressants, the antiparasitic drug hydroxychloroquine, and three cancer drugs.

Although these findings require further confirmation in humans, they represent a crucial step in protecting patients from potentially harmful drug-induced B1 deficiencies in the future.

“These results will not only help to improve the monitoring of patients taking these drugs, but could also help to develop new drugs that do not have this side effect,” Löw explained. “We believe our research could also serve as a basis for studying how drugs interact with similar transporters in the human body. In the long term, it could also guide the design of future drugs that can effectively target specific organs.”