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Physical Characterization of Vernix Caseosa: Implications for Biological Function
Başlık:
Physical Characterization of Vernix Caseosa: Implications for Biological Function
Yazar:
Joseph, Wael R., author.
ISBN:
9780438023253
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (149 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: R. Randall Wickett.
Özet:
The induction of cytochrome P450 (CYP) 3A enzymes (human isoform, CYP3A4) is a common cause of serious drug interactions. Recent cloned pregnane X receptor (PXR) is suggested to be a key transcription factor regulating CYP3A expression. We hypothesized that docetaxel and paclitaxel, two structurally similar taxane anti-cancer drugs, differ in their potential to induce CYP3A and in activating PXR. Employing primary mouse, rat and human hepatocytes, we assessed the influence of taxanes, relative to known CYP3A inducers, rifampicin and phenobarbital, on the CYP3A activity (rate of testosterone 6', CYP3A-specific immunoreactive protein (Western-blot analysis) and mRNA levels (Northern-blot analysis). We then determined the differences in the hepatocyte uptake and the magnitude of PXR activation (employing cell based reporter assays) by docetaxel and paclitaxel. Finally, employing wild type and PXR null mice we probed the in vivo PXR involvement in CYP3A induction by taxanes. We observed that while paclitaxel and docetaxel both significantly induced CYP3A in mouse and rat hepatocytes, only paclitaxel induced CYP3A in human hepatocytes. Furthermore, while paclitaxel and docetaxel both considerably activated mouse PXR, human PXR activation by docetaxel was markedly lower compared to paclitaxel. Moreover, the CYP3A induction by taxanes in wild-type C57Bl6 mice was completely abolished in PXR null mice. Another importance observation was that the uptake of paclitaxel in human hepatocytes was markedly higher than that of docetaxel. Taken together, our studies have made several very important observations. Firstly, docetaxel has markedly reduced potential to induce CYP3A4 in humans compared to paclitaxel, which suggests that docetaxel is a safer drug to use. Secondly, both pharmacokinetic (cellular uptake) and pharmacodynamic (PXR activation) differences may account for the observed differences in CYP3A induction by paclitaxel and docetaxel. PXR activation assays may be employed as an initial screen for the development of the next generation of taxanes.
Notlar:
School code: 0045
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(684115.1) | 684115-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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