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Compound corrects iron-delivery defects

May 11, 2017

Iron is an essential element for life. Red blood cells rely on iron to create heme and hemoglobin, the protein required to transport oxygen in our body. Iron is transported and shuttled to the right places in the body through an elaborate series of reactions and processes -- but when iron transportation goes wrong, the result can be too little or too much iron, resulting in diseases such as iron deficiency anemia (too little), hemochromatosis (too much) or sideroblastic anemia (too much in the wrong organelle). In a paper published May 12 in Science, investigators from Brigham and Women's Hospital, in collaboration with colleagues at University of Illinois Champaign-Urbana, describe a compound known as Hinokitiol which can correct iron-delivery defects in preclinical models. Their study lays the groundwork for investigating Hinkitiol's full potential beyond cellular and model organisms.

"The long-term therapeutic implications of our work with Hinokitiol points to potentially using this chemical to correct anemias caused by genetic deficiencies of iron transporters required for normal red cell formation," said co-corresponding author Barry Paw, MD, PhD, of BWH's Division of Hematology. "At the same time, Hinokitiol has the potential to correct iron-overload syndromes, such as hemochromatosis. More extensive clinical trials are necessary to work out the full potential of Hinokitiol and to identify potential toxicities that we have not identified using preclinical models."

Hinokitiol is a natural product found in the wood of trees. Originally isolated from the Taiwanese hinoki tree, this small molecule is also found in cedar wood.

The research team initially studied the properties of Hinokitiol in yeast - a classic model organism for studying biological processes, such as iron transport, that have been conserved across evolution. Collaborators at University of Illinois found that the compound could transport iron across the yeast cellular membrane in mutant yeasts lacking their major iron uptake transporters. BWH investigators provided mouse erythroid (red) blood cells as well as zebrafish mutants, both of which lacked the ability to transport iron. When the team administered Hinokitiol in these models as well as rodent models, they found that it remedied the blocked iron on the outside of the cells, or subcellular organelles, correcting anemia at the cellular level.

"We found that Hinokitiol can restore iron transport within cells, out of cells or both," said Paw. "It can also promote iron gut absorption and the creation of hemoglobin in some of our models. These findings suggest that small molecules like Hinkitiol that can mimic the biological function of a missing protein may have potential for treating human diseases."
This work was funded by the National Institutes of Health (BWH) and the Howard Hughes Medical Institute (University of Illinois at Urbana-Champaign).

Brigham and Women's Hospital

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