Pharmacological properties of dibenzo[a,c]cyclooctene derivatives isolated from Fructus Schizandrae chinensis. II. Induction of phenobarbital-like hepatic monooxygenases.

Schizandrin (Sin) A, B and C, Schizandrol (Sol) A and B and Schizandrer (Ser) A and B were isolated from Fructus Schizandrae chinensis, a traditional Chinese tonic. These components are the derivatives of dibenzo[a,c]cylooctene. Dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-biphenyl-2,2'-dicarboxylate (DDB) is an intermediate for synthesizing Sin C. The effect of these compounds on rat liver microsomal monooxygenases and epoxide hydrolase has been studied. Among these compounds, Sin B, Sin C, Sol B and DDB significantly increased rat liver cytochrome P-450 concentration, NADPH-cytochrome c reductase, benzphetamine and aminopyrene demethylase activities. The four compounds also markedly stimulated proliferation of smooth endoplasmic reticulum of liver cells. Metyrapone (1 mM) inhibited to a same extent (about 50%) the activity of aminopyrene demethylase of microsomes from rats treated by Sin B, Sin C, Sol B, DDB and phenobarbital (PB). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of liver microsomal preparations showed that Sin B and Sol B induce a major protein band of P-450 similar to that induced by PB. In addition, the effect of Sin B-, Sol B- and DDB-treated rat liver microsomes on [G-3H]-benzo[a]pyrene (BP) metabolism and covalent binding of reactive metabolites to DNA, in vitro, resembles that of PB. Dual induction of rats by Sol B and BP decreased mutagenicity of BP.