Notopterygium forbesii Boiss Extract and Its Active Constituents Increase Reactive Species and Heme Oxygenase-1 in Human Fetal Hepatocytes: Mechanisms of Action

Notopterygium forbesii Boiss (NF) has been used as a traditional Chinese medicine for the treatment of common cold and rheumatism. However, there has been limited research on the biological properties of NF, and the mechanisms of action remain unknown. Here, we aimed to study the mechanism of NF-induced heme oxygenase-1 (HO-1) in human fetal hepatocytes (HFHs) and to identify the constituents responsible. Exposure of HFHs to NF causes oxidative stress with the accumulation of reactive species, which in turn leads to the phosphorylation of p38 MAPK and nuclear accumulation of Nrf2 transcription factor, and eventually increased levels of HO-1 mRNA and protein. The increases in reactive species and HO-1 protein are inhibited by agonists of glucocorticoid receptors (GR), such as RU28362, prednisolone, and dexamethasone, as well as by N-acetyl-L-cysteine and SB203580 (a p38 inhibitor), suggesting a role of GR in NF-induced increases in reactive species and HO-1. Assay-guided fractionation of NF led to three active compounds, phenethyl ferulate, bergaptol, and isoimperatorin, that were found to increase oxidative stress and HO-1 protein levels in HFHs. The induction of HO-1 protein in response to moderate oxidative stress may explain some of the beneficial pharmacological effects of NF.