Time and dose relationships between schisandrin B- and schisandrae fructus oil-induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice

Abstract

BackgroundSchisandrin B (Sch B), a dibenzocyclooctadiene compound, is isolated from schisandrae fructus (SF). This study was conducted to compare the time- and dose-response between Sch B- and SF oil (SFO)-induced changes in hepatic and serum parameters in mice.MethodsInstitute of Cancer Research (ICR) mice were given a single oral dose of Sch B (0.125–2 g/kg) or SFO (0.3–5 g/kg). Serum alanine aminotransferase (ALT) activity, hepatic malondialdehyde, and triglyceride (TG) levels were measured at increasing time intervals within 6–120 hours postdosing.ResultsSerum ALT activity was elevated by 60%, with maximum effect (Emax) =45.77 U/L and affinity (KD) =1.25 g/kg at 48–96 hours following Sch B, but not SFO, treatment. Sch B and SFO treatments increased hepatic malondialdehyde level by 70% (Emax =2.30 nmol/mg protein and KD =0.41 g/kg) and 22% (Emax =1.42 nmol/mg protein and KD =2.56 g/kg) at 72 hours postdosing, respectively. Hepatic index was increased by 16%–60% (Emax =11.01, KD =0.68 g/kg) and 8%–32% (Emax =9.88, KD =4.47 g/kg) at 12–120 hours and 24–120 hours after the administration of Sch B and SFO, respectively. Hepatic TG level was increased by 40%–158% and 35%–85%, respectively, at 12–96 hours and 6–48 hours after Sch B and SFO treatment, respectively. The values of Emax and KD for Sch B/SFO-induced increase in hepatic TG were estimated to be 22.94/15.02 μmol/g and 0.78/3.03 g/kg, respectively. Both Sch B and SFO increased serum TG (up to 427% and 123%, respectively), with the values of Emax =5.50/4.60 mmol/L and KD =0.43/2.84 g/kg, respectively.ConclusionThe findings indicated that Sch B/SFO-induced increases in serum/hepatic parameters occurred in a time-dependent manner, with the time of onset being serum TG level < hepatic TG level < hepatic index < serum ALT activity. However, the time of recovery of these parameters to normal values varied as follow: serum TG level < hepatic TG level and liver injury < hepatic index. The Emax and affinity of Sch B on tissue/enzyme/receptor were larger than those of SFO.

The Cytochrome P450-Mediated Metabolism Alternation of Four Effective Lignans From Schisandra chinensis in Carbon Tetrachloride-Intoxicated Rats and Patients With Advanced Hepatocellular Carcinoma

“…Most of the previous studies reported that the SC active lignans had hepatoprotective effect against many kinds of liver diseases. However, it was recently revealed that schisandrin B and schisandrae fructus oil could induce hepatotoxicity associated with elevations in hepatic and serum triglyceride levels in mice (Zhang et al, 2014 ). In addition, it was found that SC lignans exhibited inhibition or induction effects on CYP450s, the most important drug metabolism enzymes, causing herbal-drug interaction which might affect the drug therapy or safety (Wang et al, 2014 ).…”

“…Many pharmacological studies revealed that SC and schisandra lignans, the major effective components, showed various beneficial biological activities including hepatoprotection against viral and various hepatotoxins, tranquilization, hypnogenesis, anticonvulsive and neuro-protective effects, and so on (Lu and Liu, 1992 ; Fujihashi et al, 1995 ; Zhu et al, 2016 ; Szopa et al, 2017 ). However, it was recently reported that schisandrin B and schisandrae fructus oil could elevate hepatic and serum triglyceride levels, heighten serum alanine aminotransferase (ALT) activity, and eventually induce hepatotoxicity (hypertriglyceridemia, hepatomegaly and liver damage) in mice (Zhang et al, 2014 ). SC extracts exhibited inhibitive or inductive effects on rat hepatic cytochrome P450 (CYP450) enzymes and caused herb-drug interaction mediated by CYP450s (Wang et al, 2014 ).…”

Biochemical mechanism underlying hypertriglyceridemia and hepatic steatosis/hepatomegaly induced by acute schisandrin B treatment in mice

“…Our previous study showed that fenofibrate, a widely prescribed TG-lowering agent, could eliminate Sch B- and Sch oil-induced hypertriglyceridemia, hepatic steatosis, and liver injury [20, 31]. It has been demonstrated that Sch B caused hepatotoxicity (increase in serum ALT activity [19] via PI3K/AKt/mtOR signaling pathway in our previous study [32]. We consider that Sch B-induced hypertriglyceridemia and hepatic steatosis resulted from the lipolysis (decrease in adipocyte size and increase in serum NEFA) and exogenous sources (increase in serum Apo B48).…”

“…However, the use of Schisandrae Fructus and its active components is more popular in China and other Asian countries which are strongly influenced by the practice of Chinese medicine. Previous studies from our laboratory have demonstrated that Sch B treatment increased serum and hepatic TG levels, serum alanine aminotransferase (ALT) activity and hepatic mass in mice, suggestive of a mouse model of hypertriglyceridemia combined with hepatic steatosis and injury [19–21]. It is well known that TG in bloodstream is derived from exogenous (dietary sources) and endogenous (synthesis in liver using fatty acids) pathways.…”

A comparative study between Wuweizi seed and its post-ethanol extraction residue in normal and hypercholesterolemic mice

“…FSC has previously been reported to have a wide spectrum of biological effects, including protecting against chemically and virally induced hepatic injury [ 13 , 14 ], improving insulin sensitivity [ 15 ], protecting against oxidative damage [ 16 ], producing sedative–hypnotic activity and anti-inflammatory effects [ 17 , 18 ]. Our previous works have demonstrated that FSC extract and FSC-related compounds significantly altered lipid metabolism in mice [ 19 – 23 ]. In the present study, we endeavored to evaluate the effects of dietary supplementation with FSC seed (FSC-S) and the post-ethanol extraction residue of FSC-S (FSC-SpEt) on serum and hepatic lipid/glucose (GLU) contents in both normal diet-fed (ND) and high cholesterol/bile salt diet-fed (HCBD) mice, an animal model of hypercholesterolemia (HCL).…”