hERG channel blockade and additive interactions of magnolol and honokiol from Magnolia species

The Magnolia officinalis cortex (the dried bark known as "Houpo") is widely used in traditional Chinese medicine (TCM). In this study, we discovered some potential off-target effects of M. officinalis due to the blocking effects on hERG (human Ether-a-go-go-Related Gene) channels by magnolol and honokiol, two main active chemicals of M. officialis. This research investigated the modulatory effects of two neolignans and their cooperative effects on hERG channels using manual whole-cell patch-clamp techniques. Results showed that magnolol and honokiol blocked hERG currents with IC₅₀s of 5.2 ± 0.3 µM and 4.7 ± 0.5 µM. The blockade induced by two neolignans not only increased with increasing depolarizing strengths and durations but also significantly altered hERG activation and inactivation properties, which suggested a preferential binding to open or inactivated states. The reduced blockade by the less inactivating S631 A mutation supported their inactivation preference. We also discovered an overall additive effect of two neolignans, which might increase potential cardiotoxic risks. To our knowledge, this is the first report of the additive effects of two chemicals from one herb on hERG channels and also the first discovery of neolignans acting as hERG blockers. In conclusion, magnolol and honokiol can block hERG channels in a similar way and an additive effect exists among them. The results add to the understanding of the cardiovascular risk profile of Magnolia herbs.