Inductive effects of artemisinin-based antimalarials on nuclear receptor CAR and CYP2B in rats liver
Shuqi Zhang · Chinese Remedies & Clinics · 2010
Objective To investigate the inductive effects of artemisinin (ART) and dihydroartemisinin (DHA) on nuclear receptors and drug-metabolizing CYP450s in rats liver. Methods SD rats were randomly divided into eight groups: oral ART group (80 mg·kg-1·d-1 for 5 days), oral DHA group (10 mg·kg-1·d-1 for 5 days), oral vehicle control group, intravenous ART group (6 mg·kg-1·d-1 for 5 days), intravenous DHA group (5 mg·kg-1·d-1 for 5 days), intravenous vehicle (ART) control group, intravenous vehicle (DHA) control group and blank control group. All rats were sacrificed and harvested for livers at 24 hours after the last dose. The mRNA expression of nuclear receptors and CYP450s in rat liver was determined by SYBR green real-time quantitative PCR. Results Compared to vehicle control group and blank control group, mRNA expression of both CYP2B1 and CAR in oral ART treated rats was in- creased significantly (P0.01). CYP2B1 mRNA expression was also significantly increased in oral DHA rats (P0.01). Yet ART or DHA-intravenously treated rats did not show significant changes in mRNA expression of both nuclear receptor and CYP450s, compared to control groups. Conclusion Multiple oral doses of artemisinin-based drugs appeared to activate nuclear receptor CAR which in turn up-regulated CYP2B1 mRNA expression and promote metabolism of the drugs, whereas multiple intravenous doses of ART or DHA had no evident inductive effects on metabolism enzymes. This suggested that inductive action of artemisinin-based drugs may be based on first-pass effect.