Schisandrin B inhibits cell growth and induces cellular apoptosis and autophagy in mouse hepatocytes and macrophages: implications for its hepatotoxicity.
A number of drugs and herbal compounds have been documented to cause hepatoxicity. Schisandrin B (Sch B) is an active dibenzocyclooctadiene isolated from Schisandrae fructus, with a wide array of pharmacological activities. However, the potential hepatotoxicity of Sch B is a major safety concern, and the underlying mechanism for Sch B-induced liver toxic effects is not fully elucidated. In the present study, we aimed to investigate the liver toxic effects and the molecular mechanisms of Sch B in mouse liver and macrophage cells. The results have shown that Sch B exhibits potent grow inhibitory, proapoptotic, and proautophagic effects in AML-12 and RAW 264.7 cells. Sch B markedly arrested cells in G1 phase in both cell lines, accompanied by the down-regulation of cyclin dependent kinase 2 (CDK2) and cyclin D1 and up-regulation of p27 Kip1 and checkpoint kinase 1. Furthermore, Sch B markedly increased the apoptosis of AML-12 and RAW 264.7 cells with a decrease in the expression of B-cell lymphoma-extra-large and (Bcl-xl) B-cell lymphoma 2 (Bcl-2), but an increase in the expression of B-cell lymphoma 2-associated X protein (Bax). Sch B promoted the cleavage of caspase 3 and poly-adenosine diphosphate-ribose polymerase (PARP) in both cell lines. Additionally, Sch B significantly induced autophagy of AML-12 and RAW 264.7 cells. Sch B inhibited the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, as indicated by their altered phosphorylation, contributing to the proautophagic effect of Sch B. Taken together, our findings show that the inducing effects of Sch B on cell cycle arrest, apoptosis, and autophagy may contribute to its liver toxic effects, which might provide a clue for the investigation of the molecular toxic targets and underlying mechanisms for Sch B-induced hepatotoxicity in herbal consumers. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Sch B for clinical use.
Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
Yi
Y
Zhang
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
Zhi-Wei
ZW
Zhou
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
Hua
H
Jin
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
Chengbin
C
Hu
Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People's Republic of China.
Zhi-Xu
ZX
He
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, People's Republic of China.
Zhi-Ling
ZL
Yu
Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China.
Kam-Ming
KM
Ko
Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA.
Tianxin
T
Yang
Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People's Republic of China.
Xueji
X
Zhang
Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
Si-Yuan
SY
Pan
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
Shu-Feng
SF
Zhou
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D034242:Cyclooctanes / Q000494:pharmacology / Q000633:toxicity; D016193:G1 Phase / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects*; D017705:Lignans / Q000494:pharmacology* / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects; D011083:Polycyclic Compounds / Q000494:pharmacology* / Q000633:toxicity*; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D034242:Cyclooctanes; D017705:Lignans; D011083:Polycyclic Compounds; C015499:schizandrin B
AML-12 cell; Bcl-2; RAW 264.7 cell; herbal medicine; liver toxicity; mTOR