Genistein is an investigational compound that is under preclinical evaluation for the treatment of cystic fibrosis (CF). Genistein is a naturally occurring compound first isolated in 1899 from a flowering plant called dyer’s broom (Genista tinctoria). Genistein is an isoflavone, or plant-derived, compound that exhibits properties similar to estrogen, the female hormone responsible for regulating secondary female sexual characteristics. For this reason, isoflavones are also referred to as phytoestrogens.

How genistein works

CF is a genetic condition caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. These mutations compromise the function of the CFTR protein, responsible for controlling the transport of chloride ions across cell membranes, resulting in the production of thick, obstructive, and dysfunctional mucus within the secretory cells of the body.

The molecular mechanism through which CFTR function is compromised can vary based on the type of mutation occurring within the gene. Whereas some CFTR mutations can cause problems with protein production and folding, others can cause a direct functional impairment in chloride transport across an existing channel.

Many preclinical studies have hinted the utility of genistein as a possible CFTR potentiator — a compound that facilitates the transport of chloride ions across the CFTR channel protein by holding it open for longer. CFTR potentiators are a subclass of CFTR modulators.

The exact mechanism of genistein-induced potentiation is debatable and there are many mechanisms of actions that have been proposed to explain genistein activity on the CFTR channel.

Research about genistein as a potential treatment for CF

There are currently no clinical trials investigating the use of genistein for the treatment of CF, but there have been many pre-clinical studies investigating the potential benefits of the compound in animal models of the disease.

In contrast to the so-called delta F508 mutation, which impairs the physical transport of the CFTR channel to the cell surface, another mutation called the G551D mutation impairs the direct conductance of chloride ion across the channel. G551D is the third-most common mutation causing CF. A study conducted in 1999 revealed that the impairment of chloride transport due to this mutation can be rescued by treatment with genistein.

Another study conducted in 1997 showed that genistein can potentiate the activity of both normal and the delta F508-mutation-bearing CFTR channels. The interpretation of these results is difficult since many studies have shown that genistein’s ability to potentiate across CFTR channels varies significantly according to dose.

A bioinformatics study has predicted five possible genistein binding sites on the CFTR channel. Such studies could provide critical information that can help chemists in designing treatments like genistein, which can dock onto the CFTR channel. Such docking compounds can be designed to trigger slight changes in the protein structure and facilitate the transport of chloride ions and water.

Constipation is a frequent symptom in CF patients because of altered intestinal fluid composition brought about by a defect in CFTR channels in the secretory cells lining the digestive system. A recent study in a rodent model has shown that genistein supplementation dramatically reduced the need for laxatives.

study led by researchers at the Division of Pulmonary Medicine at Cincinnati Children’s Hospital Medical Center has presented some preliminary evidence to support the idea that consumption of genistein might reduce CF symptoms in patients bearing a mutation called S1045Y in the CFTR gene.

A recent preclinical study led by researchers at the Department of Pediatric Pulmonology at Erasmus University Medical Centre Rotterdam in the Netherlands suggests that combining Kalydeko (ivacaftor), genistein, and curcumin can restore CFTR-dependent fluid secretion in primary CF cells.

One clinical trial (NCT00590538) was initiated in 2003 with the goal of assessing the efficacy of combining phenylbutyrate and genistein for the treatment of CF patients who carry the delta F508 mutation. The study measured changes in chloride transport upon treatment, but the results were inconclusive and the trial was wrapped up in 2008.

In summary, most of the research on genistein is of preclinical nature and further testing of this compound will be required for its successful use in the clinic.

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