Dimethyl diphenyl bicarboxylate (dimethyl-4,4'-dimethyloxy-5,6,5',6'-dimethylene-dioxy-di phe nyl-2,2'- bicarboxylate, DDB), a synthetic mimic of the
natural product schizandrin C, is used in China as a hepatoprotective agent to improve the liver functions of patients with
hepatitis or under
cancer chemotherapy. In this study, we investigated the effects of
DDB on liver microsomal
drug-metabolizing
enzymes. When male Sprague-Dawley rats were treated with a daily intragastric dose of
DDB (200 mg.kg-1) for 3 d, the microsomal
pentoxyresorufin dealkylase activity and P-450 2B1
protein levels were markedly increased. The fold increase was lower than that by
phenobarbital (75 mg.kg-1, ip once daily x 3 d). The level of P-450 2B1
mRNA was elevated by
DDB but the magnitude of the elevation was much less than that caused by
phenobarbital.
DDB also increased the rates of
testosterone hydroxylation at positions 16 beta, 16 alpha, 6 beta, and 2 beta as well as the rate of
ethoxyresorufin dealkylation, suggesting moderate increases in the levels of P-450 3A and P-450 1A1 in addition to the huge increase in P-450 2B1. The level of
glutathione S-transferase was also slightly increased, but the levels of P-450 2E1 and
NAD(P)H:
quinone oxidoreductase were not changed. The results indicate that
DDB is an inducer of P-450 2B1.