Saikosaponins with similar structures but different mechanisms lead to combined hepatotoxicity

TL;DR

This study compares the mechanisms of different saikosaponins from Radix Bupleuri, revealing distinct pathways leading to hepatotoxicity and their combined effects on liver cells and mitochondria.

Contribution

It provides a systematic comparison of structurally similar saikosaponins, uncovering their different molecular mechanisms of hepatotoxicity.

Findings

SSb2 causes mitochondrial permeability transition and membrane potential collapse.

SSd destroys plasma membrane and activates caspase-1.

Combined hepatotoxicity of SSb2 and SSd is additive.

Abstract

Radix Bupleuri is a hepatoprotective traditional Chinese medicine (TCM) used for thousands of years in clinical, which was reported to be linked with liver damage. Previous studies have revealed that saikosaponins are the major types of components that contribute to the hepatotoxicity of Radix Bupleuri. However the underlying molecular mechanism is far from being understood. In order to clarify whether these structural analogues exert toxicity effects through the same molecular targets, a systematic comparison study was done in this paper. The effects of SSa, b2, c, and d on isolated rat liver mitochondria and human hepatocyte L02 cells were explored, respectively. The collective results indicated that although saikosaponins share the similar structures but they have quite different mechanisms. SSb2 and SSd showed most serious damage on the function of mitochondria and survival rate of cell, respectively. SSb2 could cause mitochondrial permeability transition pore (mPTP) opening and collapse of mitochondrial membrane potential ({\Delta}{\Psi}m) by impairing the mitochondrial respiratory chain complex III. While SSd destroyed plasma membrane and led to the release of lactate dehydrogenase (LDH) mainly through activating caspase-1. Furthermore, the combine index (CI) demonstrated that the combined hepatotoxicity of SSb2 and SSd could be additive. This finding might yield more in depth understanding of hepatotoxicity of Radix Bupleuri possess many different saikosaponins.