Muscone Induces CYP1A2 and CYP3A4 Enzyme Expression in L02 Human Liver Cells and CYP1A2 and CYP3A11 Enzyme Expression in Kunming Mice

Aim: To examine the effect of synthetic muscone on the expression of CYP1A2 and CYP3A4 enzymes in human liver L02 cells and in the liver tissue of Kunming mice. Methods: The L02 hepatic cell line was used to study the effect of low (10(-4) mu mol/L), middle (10(-3) mu mol/L), and high concentrations (10(-2) mu mol/L) of muscone on the expression of CYP1A2 and CYP3A4 enzymes. In addition, the cytochrome P450 (CYP) expression was investigated in Kunming mice after the administration of 10 mg/kg (low), 50 mg/kg (middle), and 100 mg/kg (high) dose of muscone for 6 days. A mixture of phenobarbital (30 mg/kg) and beta-napthoflavone (80 mg/kg) was used as positive control and the effects of the compounds on CYP expression were investigated at the end of 6-and 12-day periods. Results: Muscone induced the expression of CYP1A2 (middle and low concentrations) and of CYP3A4 (high concentration) enzymes in L02 cells. In vivo, administration of muscone in Kunming mice revealed significant weight reduction at the end of 6-and 12-day periods (middle and high doses, respectively), compared to the control group (p < 0.05). Liver toxicity scores indicated that the liver injuries in the positive control and high doses of muscone group were significantly higher in the 6-and 12-day periods, compared to those in the blank control group (p < 0.05). Furthermore, muscone induced CYP1A2 and CYP3A11 expressions in Kunming mice at the middle dose and all doses during the 12-day period as demonstrated by immunoblotting experiments. A low dose of mucone induced the CYP enzyme expression more rapidly, whereas a high dose of muscone caused the longest inductive effect. The results were confirmed by immunohistochemistry experiments and real-time PCR studies, where similar patterns of muscone-mediated inductive effects were noted. Conclusions: Muscone induces CYP1A2 and CYP3A4 expression in liver cells in vitro and in vivo. In addition, it exhibits liver toxicity in Kunming mice at concentrations higher than 50 mg/kg. The CYP-inductive effect that is caused by muscone encompasses a 6-to 12-day period of activity after drug administration as demonstrated by follow-up in vivo studies. (C) 2017 S. Karger AG, Basel