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Effects of oral genistein in mice
Anita Bhandari1, Susan E Crawford, Lijun Huang
1Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4399, USA. bhandari@email.chop.edu
Abstract:
In cell culture systems, genistein, a soy-derived isoflavone with chemopreventive and estrogenic effects, enhances cAMP-dependent activation of the most common cystic fibrosis-causing mutation, deltaF508-CFTR, by as much as 20-fold. DeltaF508-CFTR is present in the apical membrane at far lower levels than wild-type CFTR. If genistein can enhance cyclic AMP-dependent activity in vivo, the presence of deltaF508-CFTR, at even a few percent of wild-type levels, might permit genistein to be of therapeutic benefit to cystic fibrosis patients with this mutation. Before determining if oral genistein would be of benefit in mice with a deltaF508 mutation in the murine CFTR gene, a maximal dose of oral genistein with minimal side effects needed to be established. Accordingly, C57Bl/6 mice pups were randomly weaned onto soy-free diet, AIN-76, containing between 0 and 1.0 g/kg genistein and allowed to feed ad libitum for 3 weeks. Genistein had no significant effects on growth rates of either male or female mice. Histology of the lung, heart, kidney, liver, and intestine revealed no significant genistein-dependent changes in morphology. When mice on a 1.0 g/kg of genistein diet were sacrificed in the morning, the mean level of serum genistein was 1.4+/-0.2 micro moles/L. Serum genistein increased during the daylight hours reaching a maximum of 7.5+/-0.6 micro moles/L in the early evening. Our results demonstrate that dietary genistein is not inhibitory to growth or caloric intake and up to 1.0 g/kg ad libitum genistein causes no significant organ specific abnormalities.
Insights
Genistein, a soy isoflavone, shows promise for cystic fibrosis treatment by enhancing deltaF508-CFTR function. Studies show dietary genistein up to 1.0 g/kg is safe in mice, with no adverse effects on growth or organs.
Area of Science:
- Biochemistry
- Pharmacology
- Genetics
Background:
- Genistein, a soy isoflavone, exhibits chemopreventive and estrogenic properties.
- In vitro studies demonstrate genistein enhances cAMP-dependent activation of deltaF508-CFTR, the most common cystic fibrosis mutation, by up to 20-fold.
- DeltaF508-CFTR is found at lower levels in the apical membrane compared to wild-type CFTR.
Purpose of the Study:
- To establish a maximal safe dose of oral genistein with minimal side effects in mice.
- To assess the potential therapeutic benefit of genistein for cystic fibrosis patients with the deltaF508 mutation.
Main Methods:
- C57Bl/6 mice pups were weaned onto a soy-free diet (AIN-76) with varying genistein concentrations (0-1.0 g/kg) for 3 weeks.
- Growth rates, organ histology (lung, heart, kidney, liver, intestine), and serum genistein levels were analyzed.
- Serum genistein levels were measured at different times of day to assess pharmacokinetics.
Main Results:
- Genistein administration (up to 1.0 g/kg) did not significantly affect mouse growth rates or caloric intake.
- Histological examination revealed no significant genistein-dependent abnormalities in major organs.
- Serum genistein levels showed a diurnal pattern, peaking in the early evening.
Conclusions:
- Dietary genistein up to 1.0 g/kg is well-tolerated in mice, showing no adverse effects on growth or organ morphology.
- These findings support further investigation into the therapeutic potential of oral genistein for cystic fibrosis treatment.
- Establishing a safe dosage is a crucial step before in vivo efficacy studies in cystic fibrosis models.