Additive Inhibition of HERG Channels Expressed in Xenopus Oocytes by Antipsychotic Drugs and Citrus Juice Flavonoid...

Citrus juice has been shown to cause QT prolongation in electrocardiograms of healthy volunteers, and naringenin, a major flavonoid found in citrus juice, has been identified as the potent inhibitor of human ether-a-go-go-related gene (HERG) channels as the cause of QT prolongation. Inhibition of HERG channels and prolongation of QT interval by antipsychotic drugs such as haloperidol, chlorpromazine, and clozapine have also been shown. However, naringenin's effect on HERG channel function in conjunction with antipsychotic medications has not been investigated.

In the present study, we evaluated the effect of combining naringenin with antipsychotics on the function of HERG channels expressed in Xenopus oocytes.

When 30 µm naringenin was added to antipsychotic drugs (1 µm haloperidol, 10 µm chlorpromazine, or 10 µm clozapine), significantly greater HERG inhibition was demonstrated, compared to the inhibition caused by antipsychotic drugs alone. Co-application studies also showed that the magnitudes of inhibitions caused by naringenin + antipsychotics were similar to that predicted by the allotopic interaction model, suggesting that naringenin and antipsychotics bind to the HERG channel at different sites.

The results suggest that there is an additive interaction between antipsychotics and naringenin. Due to the potential for repolarization heterogeneity and a decrease in repolarization reserve, this additive HERG inhibition may increase the risk of arrhythmias.