My laboratory investigates the role of the nuclear receptors, CAR and PXR, in the regulation and induction of the sex-specific and sex-predominant drug-metabolizing P450s. Adverse drug reactions kill approximately 100,000 people each year, and induction of the drug metabolizing enzymes such as the P450s cause a number of these adverse drug reactions. Identification of the chemicals that induce P450s may help us predict potential adverse drug reactions, determine susceptible groups based on sex or occupation, and ultimately save lives. Nonylphenol (NP) is one of the most commonly found toxicants in the United States and Europe, and is considered a toxicant of concern because of its long half-life. Our data demonstrates that NP activates mouse and human CAR in vitro and in vivo, and in turn induces P450s involved in chemical detoxification. Preliminary data indicates that NP also activates rat, mouse, and human pregnane X-receptor (PXR) in vitro, but we have not examined the relevance of this interaction in vivo. Therefore, we will test whether NP activates PXR and induces P450s in vivo using wild-type, PXR-null, and humanized PXR (hPXR) mice. Humanized mice containing the human nuclear receptor in the place of the mouse nuclear receptor are essential in determining the significance of our observations to human health. In addition, we will determine CAR and PXR's role in maintaining gender differences, and inducing gender specific and gender predominant P450s in mice. Many of the xenobiotic-metabolizing P450s in the CYP2 and 3 families are gender predominant. We will (1) test whether CAR and PXR in part regulate or help maintain gender differences in P450 expression of several isoforms of the CYP2 and 3 families. We will (2) examine whether the toxicant NP, the CAR agonist TCPOBOP, and the PXR agonist Dexamethasone induce these P450 isoforms in a gender specific or gender predominant fashion in wild-type, CAR-null, and PXR-null mice. Furthermore, we will (3) test whether the gender predominant effects observed are pharmacologically relevant using zoxazolamine clearance and paralysis as a model for drug-toxicant interactions. Lastly, in order to determine the relevance of our in vivo observations to human health we will (4) determine if NP and other CAR/PXR activators such as dexamethasone and phenobarbital induce CYPs in a gender predominant fashion in primary human hepatocytes. We hypothesize that CAR and PXR play roles in the maintenance of the drug-metabolizing P450s and their gender predominance. Furthermore, we hypothesize that some of these P450s are induced in a gender predominant fashion by CAR and PXR agonists, which may cause pharmacologically relevant gender predominant effects.
The purpose of this project is to further characterize the nuclear receptors CAR and PXR, as well as determine if they are involved in gender differences in P450 expression and adverse drug reactions.
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