Abstract
Cytochrome P450 (CYP) downregulation is a mechanism of drug-drug interaction encountered in pharmaceutical development which is difficult to evaluate in vitro because of the scarcity of evidence. A previous clinical study of obeticholic acid (OCA) with caffeine suggested that OCA may be a useful positive control to establish a method to evaluate CYP1A2 downregulation and to investigate the mechanism of its downregulation. In the present study, we investigated the ability of OCA to downregulate CYP1A2 in human hepatocytes. OCA suppressed CYP1A2 mRNA expression and CYP1A2 enzyme activity without causing direct inhibition of CYP1A2 or cytotoxicity, suggesting that OCA downregulates CYP1A2 in vitro. OCA significantly suppressed the induction of CYP1A2 mRNA expression by omeprazole in a concentration-dependent manner, suggesting that a combination of inducers and new chemical entities would be helpful to investigate the mechanism of CYP1A2 downregulation and to evaluate the potential of new chemical entities for downregulation and investigate their downregulation mechanism. We also showed that CYP1A2 was transcriptionally downregulated by OCA and that a reduction in aryl hydrocarbon receptor mRNA expression is a possible mechanism of CYP1A2 downregulation by OCA. These results indicate that OCA would be a suitable positive control for studies of CYP1A2 downregulation.
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