title: 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: BACKGROUND
  Schisandrin 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.
  
  
  METHODS
  Institute 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.
  
  
  RESULTS
  Serum ALT activity was elevated by 60%, with maximum effect (E(max)) = 45.77 U/L and affinity (K(D)) = 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% (E(max) =2.30 nmol/mg protein and K(D) =0.41 g/kg) and 22% (E(max) = 1.42 nmol/mg protein and K D = 2.56 g/kg) at 72 hours postdosing, respectively. Hepatic index was increased by 16%-60% (E max = 11.01, K(D) = 0.68 g/kg) and 8%-32% (E(max) = 9.88, K D = 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 E max and K D 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 E(max) = 5.50/4.60 mmol/L and K D = 0.43/2.84 g/kg, respectively.
  
  
  CONCLUSIONS
  The 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 E max and affinity of Sch B on tissue/enzyme/receptor were larger than those of SFO.
authors.affiliation: Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
authors.forename: Si-Yuan
authors.initials: SY
authors.lastname: Pan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
authors.forename: Pei-Li
authors.initials: PL
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
authors.forename: Zhu-Sheng
authors.initials: ZS
authors.lastname: Chu
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, People's Republic of China.
authors.forename: Zhi-Ling
authors.initials: ZL
authors.lastname: Yu
authors.affiliation: Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China.
authors.forename: Kam-Ming
authors.initials: KM
authors.lastname: Ko
mesh_terms: D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D034242:Cyclooctanes / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D017705:Lignans / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D010938:Plant Oils / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D032141:Schisandra / Q000737:chemistry*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism*
chemical_list: D034242:Cyclooctanes; D017705:Lignans; D010938:Plant Oils; D011083:Polycyclic Compounds; D014280:Triglycerides; C015499:schizandrin B; D008315:Malondialdehyde; D000410:Alanine Transaminase
keywords: affinity; alanine aminotransaminase; hepatomegaly; maximum effect; pharmacodynamics