In vitro evaluation of Boswella serrata extract as an inhibitor of cytochrome P450 (CYP) enzymes in cryopreserved human hepatocytes and human liver microsomes

Abstract

As the use of dietary supplements increases, the potential for drug-dietary supplement interaction should be evaluated. Boswellia serrata (gum resin) has been traditionally used to treat various inflammatory diseases. Potent in vitro inhibition (≥65%) across major drug metabolizing enzymes (CYP1A2/2C8/2C9/2C19/2D6/3A4) using pooled human liver microsomes (PHLM) have been reported in the literature for levels of Boswellia serrata extract as low as 1 µg/mL. This potent and promiscuous level of inhibition by an herbal ingredient led us to question the relevance of the results in the in vitro test system used (i.e., PHLM). Our study evaluated the ability of Boswellia serrata extract to inhibit CYP2C9 and CYP3A4/5 in PHLM and in cryopreserved human hepatocytes, with the aim of understanding potential in vitro system differences in studying drug-dietary interactions. Boswellia serrata extract was evaluated as a direct and time-dependent inhibitor of CYP activity in PHLM and in pooled cryopreserved human hepatocytes. In PHLMs, Boswellia serrata extract was a direct inhibitor of CYP2C9 and CYP3A4/5 with IC50 values of 11 µg/mL and 1.4 µg/mL; respectively. Considerably less direct inhibition of CYP2C9 and CYP3A4/5 was observed when Boswellia serrata extract was tested using pooled cryopreserved human hepatocytes; IC50 values > 50 µg/mL for both enzymes. There was little or no evidence of time-dependent inhibition of CYP2C9 or CYP3A4/5 activity using either system. These data would suggest that the degree of inhibition observed with Boswellia serrata extract could be dependent upon the test system used to measure the IC50 value. Additional studies in hepatocyte test systems with known functional transport mechanisms would also be helpful in more fully assessing drug-dietary interaction potential.