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Cytochrome P450 3A metabolism in the...
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Attar, Mayssa.
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Cytochrome P450 3A metabolism in the rabbit lacrimal gland and conjunctiva.
紀錄類型:
書目-電子資源 : Monograph/item
正題名/作者:
Cytochrome P450 3A metabolism in the rabbit lacrimal gland and conjunctiva./
作者:
Attar, Mayssa.
面頁冊數:
236 p.
附註:
Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3077.
Contained By:
Dissertation Abstracts International66-06B.
標題:
Health Sciences, Pharmacology. -
電子資源:
http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3180385
ISBN:
0542204657
Cytochrome P450 3A metabolism in the rabbit lacrimal gland and conjunctiva.
Attar, Mayssa.
Cytochrome P450 3A metabolism in the rabbit lacrimal gland and conjunctiva.
- 236 p.
Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3077.
Thesis (Ph.D.)--University of Southern California, 2005.
The goal of this project was to begin mapping the drug metabolism machinery in rabbit ocular tissues and to assess their possible role in ocular physiology. Our initial focus was on cytochrome P450 3A (CYP3A), an enzyme with broad substrate specificity, in the lacrimal gland and conjunctiva. These tissues are, respectively, the point of exit for tears and the point of entry for ophthalmic drugs.
ISBN: 0542204657Subjects--Topical Terms:
1017717
Health Sciences, Pharmacology.
Cytochrome P450 3A metabolism in the rabbit lacrimal gland and conjunctiva.
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Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3077.
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Thesis (Ph.D.)--University of Southern California, 2005.
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The goal of this project was to begin mapping the drug metabolism machinery in rabbit ocular tissues and to assess their possible role in ocular physiology. Our initial focus was on cytochrome P450 3A (CYP3A), an enzyme with broad substrate specificity, in the lacrimal gland and conjunctiva. These tissues are, respectively, the point of exit for tears and the point of entry for ophthalmic drugs.
520
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Preliminary characterization was conducted on naive rabbit ocular tissues using Western blot and monitoring benzyloxyquinoline metabolism. Further analysis of CYP3A was performed in lacrimal gland and conjunctiva tissues obtained from treated New Zealand white rabbits. Treated rabbits received a topical installation of 50 mu1 of vehicle, 0.1% or 1.0% dexamethasone solution to both eyes for 5 days. Changes in gene and protein expression were monitored using real-time RT-PCR and 2D gel electrophoresis, respectively. Functional activity was measured by monitoring [3H]testosterone and cyclosporine A metabolism.
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We detected NADPH-reductase and heme protein at concentrations ranging from 44.6--119 pmol/mg protein in rabbit ocular tissues. We detected CYP1A, CYP2D and CYP3A expression and activity in naive ocular tissues. Genes encoding CYP3A, in addition to pregnane-X-receptor, p-glycoprotein and androgen receptor, were expressed in the untreated lacrimal gland. The same genes, except for pregnane-X-receptor, were expressed in the untreated conjunctiva. Dexamethasone treatment increased up to 5-fold gene expression of CYP3A and p-glycoprotein in both tissues. Dexamethasone treatment suppressed androgen receptor expression by half in the lacrimal gland. Benzyloxyquinoline and [3H]testosterone metabolism increased 2--5-fold in the lacrimal gland and conjunctiva, following dexamethasone treatment. Ketoconazole, all-trans retinoic acid and cyclosporine A inhibited [ 3H]testosterone 6beta-hydroxylation, with IC50 values ranging from 3.73--435 muM, in the lacrimal gland. Finally, cyclosporine A underwent oxidative metabolism when incubated with conjunctiva microsomes.
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We describe for the first time the expression and activity of CYP3A in the rabbit lacrimal gland and conjunctiva. Such local metabolic pathways in ocular tissues may serve tissue-specific defensive functions to maintain normal physiology. Moreover, these pathways are subject to modulation by commonly prescribed ophthalmic drugs and endogenous substrates. The stage is set for future studies to understand the importance of the metabolic barrier to topical ocular drug delivery.
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http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3180385
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