Changes in the expression of drug-metabolizing enzymes can alter the therapeutic or toxicologic response to a drug and lead to serious adverse drug interactions ? a major public health problem in the US. Cytochromes P450 (CYPs) are the most prevalent drug-metabolizing enzymes and the human pregnane X receptor (hPXR) plays a central role in activating the expression of CYP. CYP3A4 catalyzes the metabolism of more than 50% of clinically used drugs. hPXR activation and CYP3A4-mediated drug metabolism occur primarily in hepatocytes. Importantly, expression of CYPs, including CYP3A4, is significantly lower in proliferating hepatocytes of regenerating livers than in quiescent hepatocytes in the normal livers. However, the molecular mechanism responsible for the reduction in levels of drug-metabolizing enzymes in proliferating hepatocytes is unknown. Repressed levels of drug-metabolizing enzymes can have a profound effect on drug efficacy and toxicity. Because liver regeneration is triggered by liver injuries caused by a large range of insults, which affect people of all ages and backgrounds, it is important to study the regulation of PXR in proliferating hepatocytes in order to predict and prevent adverse drug interactions in patients with regenerating livers. The objective of the proposed study is to determine the mechanism by which hPXR activity and CYP3A4 expression are repressed in proliferating hepatocytes. Our central hypothesis is that Cdks phosphorylate and repress hPXR activity, thereby causing the reduction of CYP expression in proliferating hepatocytes. The rationale for conducting the proposed research is that elucidating the mechanisms by which hPXR activity and CYP3A4 expression are repressed in proliferating hepatocytes will provide fundamentally novel insights into the regulation of drug metabolism and improve our understanding of the xenobiotic response, ultimately aid the prediction of the accurate dosage of drugs, and reduce the risk of adverse drug interactions. Our long-term goal is to understand how hPXR is regulated by cellular signaling pathways through phosphorylation in both normal and diseased livers in order to design more effective therapies. We plan to test our central hypothesis by the following 4 Specific Aims: (1) Identify Cdk-regulated phosphorylation sites on hPXR;(2) Determine which phosphorylation sites are causally responsible for the inhibitory effect of Cdks and how the phosphorylation affects the activity of hPXR;(3) Determine the extent to which hPXR-mediated CYP3A4 expression is repressed by Cdk during the cell cycle in proliferating hepatocytes;and (4) Determine the in vivo effect of phosphorylation on the activity of hPXR. The outcomes are expected to provide fundamental novel information on the regulation of drug metabolism and disposition in proliferating hepatocytes, and will also lay the foundation for the effective design of drug safety evaluations and therapeutic strategies.
The proposed studies aim to fill the knowledge gap in an important area of drug metabolism and disposition, which will considerably improve our understanding of xenobiotic responses as well as risk prediction and prevention of adverse drug interactions in regenerating livers that affect people of all ages and backgrounds. The proposed studies are relevant to public health because adverse drug interactions contribute considerably to therapeutic-related morbidity and mortality, a major public health problem in the US. The results from the proposed studies will ultimately contribute to improving the health of human beings.
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