Regulation of xenobiotic receptors PXR and CAR, and CYP3A: implications in drug disposition

操纵药物处置为提高药物疗效和减少药物不良反应提供了一条途径

Manipulation of drug disposition offers an avenue toward enhancing drug efficacy and reducing adverse drug effects (including drug toxicity and drug resistance, the leading causes of drug treatment failure). We study the regulation of human pregnane X receptor (hPXR), constitutive androstane receptor (hCAR), cytochromes P450 (CYP)3A4 and CYP3A5, along with their roles in drug disposition. hPXR and hCAR are nuclear receptors modulated by many structurally diverse chemicals. They transcriptionally regulate transporters and drug- metabolizing enzymes (including CYP3A4 and CYP3A5, which metabolize more than 50% of prescribed drugs) to control xenobiotic disposition and endobiotic homeostasis, and are implicated in drug effects and in the development of human diseases (e.g., diabetes and cancer). Several key gaps remain in our understanding of the regulation of hPXR, hCAR, CYP3A4, and CYP3A5. First, hPXR and hCAR display ligand promiscuity and structural flexibility, but how compounds affect receptor activities, and how the two receptors co-regulate drug disposition, remain elusive. An innovative and systematic effort is needed to develop chemical tools to dissect hPXR and hCAR regulation in detail. Second, how CYP3A4 and CYP3A5 are differentially regulated in a tissue- and disease-context–dependent manner is unknown. Our two long-term goals are 1) to comprehensively understand the regulation of hPXR, hCAR, CYP3A4, and CYP3A5 and its implications for drug disposition and human diseases, and 2) to develop chemical tools to elucidate their regulation, prevent drug toxicity, and improve drug bioavailability. We have advanced toward these goals by discovering novel mechanisms that regulate hPXR, hCAR, and CYP3A5 (including transcriptional, post-transcriptional, and post-translational regulation, and previously unknown protein–protein interactions), and by developing novel compounds that specifically target them. We will meet 3 challenges during the next five years: (1) The mechanism by which binders of hPXR or hCAR trigger varying cellular outcomes to differentially affect xenobiotic metabolism is still not well defined, hindering our ability to accurately assess drug effects. We will develop compounds and assess their mechanisms of action and in vivo efficacy. (2) The functional relation between hPXR and hCAR and the underlying mechanism remain unclear, preventing an effective modulating approach. We will fully characterize the relation and develop compounds to modulate it and xenobiotic metabolism. (3) How CYP3A4 and CYP3A5 are differentially regulated is unclear. We will develop CYP3A5-specific inhibitors, identify the regulators of CYP3A5 expression, and develop appropriate cell models and advanced technological approaches to investigate the novel roles of CYP3A5. Together, our findings will provide a broader comprehension of the regulation of hPXR, hCAR, CYP3A4, and CYP3A5; define the previously unclear functional relation between hPXR and hCAR and design paradigm-shifting approaches to modulate it; reveal novel regulation and roles of CYP3A5; and generate novel chemical compounds as leads for therapies to prevent drug toxicity and improve drug bioavailability.