Dose-response of berberine on hepatic cytochromes P450 mRNA expression and activities in mice

Berberine is an isoquinoline alkaloid isolated from the root and bark of plants such as goldenseal, Berberis, and Chinese goldthread. Berberine-containing crude drugs have been used as an antimicrobial remedy against gastrointestinal infections for thousands of years. It is also widely used in Asian countries for diabetes, hypertension, and hypercholesterolemia therapy.

Potential drug-drug interactions are of concern because of the wide usage of berberine. A few studies have reported interactions between berberine and cytochromes P450 (CYPs) in vitro, but little is known about whether berberine influences CYPs in vivo, especially after repeated administration. In this study, eight-week-old male C57BL/6 mice were given berberine orally (0, 10, 30, 100, 300 mg/kg, i.g., daily for 14 days), and the effect of berberine on over 20 major Cyps and related nuclear receptors in mice livers were examined at both the mRNA and enzyme activity levels.

In general, liver function of mice treated with various doses of berberine had no significant change, and repeated oral administration of the 3 lower doses of berberine for 14 days did not affect the expression of genes examined. However, after the highest dose of berberine (300mg/kg), Cyp3a11 and Cyp3a25 mRNA decreased 67.6 and 87.4%, respectively, whereas Cyp1a2 mRNA increased 43.2%, and enzyme activities of Cyp3a11 and Cyp2d22 decreased 67.9 and 32.4%, respectively. Cyp2a4, 2b10 and Cyp2c29 were not altered at both mRNA and enzyme activity levels.

If studies in mice extrapolate to humans, lower doses of berberine appear to present a low risk of producing drug-drug interactions as a result of changed Cyp enzyme activity. However, high doses of berberine may suppress Cyp activities and result in drug-drug interactions.