Dmd063479 1208..1217
نویسندگان
چکیده
We developed murine Cyp3a knockout (KO) chimeric mice with humanized liver expressing human P450s similar to those in humans and whose livers and small intestines do not express murine Cyp3a. This approach may overcome effects of residual mouse metabolic enzymes like Cyp3a in conventional chimeric mice with humanized liver, such as PXB-mice [urokinase plasminogen activator/severe combined immunodeficiency (uPA/SCID) mice repopulated with over 70% human hepatocytes] to improve the prediction of drug metabolism and pharmacokinetics in humans. After human hepatocytes were transplanted into Cyp3a KO/uPA/SCID host mice, human albumin levels logarithmically increased until approximately 60 days after transplantation, findings similar to those in PXB-mice. Quantitative real-time–polymerase chain reaction analyses showed that hepatic human P450s, UGTs, SULTs, and transportersmRNA expression levels in Cyp3a KO chimeric mice were also similar to those in PXBmice and confirmed the absence of Cyp3a11 mRNA expression in mouse liver and intestine. Findings for midazolam and triazolam metabolic activities in liver microsomes were comparable between Cyp3a KO chimeric mice and PXB-mice. In contrast, these activities in the intestine of Cyp3a KO chimeric mice were attenuated compared with PXB-mice. Owing to the knockout of murine Cyp3a, hepatic Cyp2b10 and 2c55mRNA levels in Cyp3a KO/uPA/SCID mice (without hepatocyte transplants) were 8.4and 61-fold upregulated compared with PXB-mice, respectively. However, human hepatocyte transplantation successfully restored Cyp2b10 level nearly fully and Cyp2c55 level partly (still 13-fold upregulated) compared with those in PXB-mice. Intestinal Cyp2b10 and 2c55 were also repressed by human hepatocyte transplantation in Cyp3a KO chimeric mice.
منابع مشابه
Validity of final examinations in undergraduate medical training
http://bmj.com/cgi/content/full/321/7270/1217 Updated information and services can be found at: These include: References http://bmj.com/cgi/content/full/321/7270/1217#otherarticles 4 online articles that cite this article can be accessed at: Rapid responses http://bmj.com/cgi/eletter-submit/321/7270/1217 You can respond to this article at: http://bmj.com/cgi/content/full/321/7270/1217#response...
متن کاملComplete deletion of the AZFb interval from the Y chromosome in an oligozoospermic man.
BACKGROUND Deletion of the entire AZFb interval from the Y chromosome is strictly associated with azoospermia arising from maturation arrest during meiosis. Here, we describe the exceptional case of an oligozoospermic man, 13-1217, with an AZFb + c (P5/distal-P1) deletion. Through the characterization of this patient, and two AZFb (P5/proximal-P1) patients with maturation arrest, we have explor...
متن کاملSeismic tests of the structure of rapidly oscillating Ap stars : HR 1217
HR 1217 is probably the best studied multiperiodic rapidly oscillating Ap star, which makes this star a test case for the seismic analysis of these complex stars. In this paper, we combine the observational data available for HR 1217 and use these data to constrain theoretical models appropriate for this star. In particular, we try to establish which unknown model parameters are the most releva...
متن کاملCrystalloid fluid therapy
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
متن کامل