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Variability in CYP3A expression and ...

Lin, Yvonne Sarah.

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Variability in CYP3A expression and metabolism: Influence of genetics and probe substrate selection.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Variability in CYP3A expression and metabolism: Influence of genetics and probe substrate selection./
Author:	Lin, Yvonne Sarah.
Description:	203 p.
Notes:	Source: Dissertation Abstracts International, Volume: 63-11, Section: B, page: 5179.
Contained By:	Dissertation Abstracts International63-11B.
Subject:	Health Sciences, Pharmacy. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3072111
ISBN:	0493920137

Variability in CYP3A expression and metabolism: Influence of genetics and probe substrate selection.
Lin, Yvonne Sarah.

Variability in CYP3A expression and metabolism: Influence of genetics and probe substrate selection. - 203 p.

Source: Dissertation Abstracts International, Volume: 63-11, Section: B, page: 5179.

Thesis (Ph.D.)--University of Washington, 2002.

Considerable effort has been directed to the study of one of the main drug metabolizing enzyme subfamilies, cytochrome P450 3A (CYP3A). The main adult isoforms, CYP3A4 and CYP3A5, are found in liver and small intestine where they contribute to the systemic and oral clearance of many drugs. Although large interindividual differences in CYP3A-mediated drug metabolism have been noted, the biological basis for this interindividual variability is not well understood.

ISBN: 0493920137Subjects--Topical Terms:

1017737
Health Sciences, Pharmacy.

Variability in CYP3A expression and metabolism: Influence of genetics and probe substrate selection.
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100 1 $a Lin, Yvonne Sarah. $3 1952639
245 1 0 $a Variability in CYP3A expression and metabolism: Influence of genetics and probe substrate selection.
300 $a 203 p.
500 $a Source: Dissertation Abstracts International, Volume: 63-11, Section: B, page: 5179.
500 $a Chair: Kenneth E. Thummel.
502 $a Thesis (Ph.D.)--University of Washington, 2002.
520 $a Considerable effort has been directed to the study of one of the main drug metabolizing enzyme subfamilies, cytochrome P450 3A (CYP3A). The main adult isoforms, CYP3A4 and CYP3A5, are found in liver and small intestine where they contribute to the systemic and oral clearance of many drugs. Although large interindividual differences in CYP3A-mediated drug metabolism have been noted, the biological basis for this interindividual variability is not well understood.
520 $a Our work focused on identification of the causal mutation for the polymorphic expression of CYP3A5. The CYP3A5*3 allele confers low CYP3A5 protein expression as a result of improper mRNA splicing and reduced translation of a functional protein. We evaluated the transcriptional control of CYP3A5 expression and the association between CYP3A5 genotype and midazolam hydroxylation phenotype in liver and small intestines from white donors.
520 $a In a series of experiments, we compared the functional activity of cDNA-expressed CYP3A4 and CYP3A5 towards five structurally-diverse CYP3A substrates: midazolam, testosterone, dextromethorphan, lidocaine and erythromycin. In addition, we confirmed the utility of these substrates as CYP3A probes in human liver microsomal incubations.
520 $a We established that a single blood sample taken at 4-hours following an intravenous or oral midazolam dose is an excellent predictor of total midazolam clearance in a retrospective analysis of data from 224 healthy volunteers. The single-point approach may offer an efficient means to phenotype and identify individuals with important genetic polymorphisms that affect CYP3A activity.
520 $a In a clinical study, we determined whether the wide interindividual variability seen in CYP3A-mediated drug metabolism may be partially attributed to the polymorphic expression of CYP3A5 in healthy Chinese and white volunteers. We determined the effect of CYP3A5 genotype, gender and ethnicity on 4-hour intravenous and oral midazolam concentrations and total urinary 1'-hydroxymidazolam recovery.
520 $a In summary, the polymorphic expression of CYP3A5 appears to affect CYP3A-dependent drug clearance. For individuals expressing high levels of CYP3A5, the contribution of CYP3A5 to in vitro and in vivo metabolism could be significant. It is likely that the CYP3A5 expression (and associated genetic haplotypes) may partially explain the interindividual variability seen in CYP3A-mediated metabolism.
590 $a School code: 0250.
650 4 $a Health Sciences, Pharmacy. $3 1017737
650 4 $a Health Sciences, Pharmacology. $3 1017717
650 4 $a Biology, Molecular. $3 1017719
690 $a 0572
690 $a 0419
690 $a 0307
710 2 0 $a University of Washington. $3 545923
773 0 $t Dissertation Abstracts International $g 63-11B.
790 1 0 $a Thummel, Kenneth E., $e advisor
790 $a 0250
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3072111