1987 Fiscal Year Final Research Report Summary
Studies on drug metabolism in ocular tissues ----- Oxygenation by cytochrome P-450 and glutathione conjugation
| Project/Area Number |
61480366
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Ophthalmology
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| Research Institution | OSAKA UNIVERSITY |
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Principal Investigator |
MANABE Reizo Osaka University Medical School Prcfesscr, 医学部, 教授 (00028333)
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| Co-Investigator(Kenkyū-buntansha) |
KISHIDA Kenichi Osaka University Medical School Iecturer, 医学部, 講師 (80028563)
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| Project Period (FY) |
1986 – 1987
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| Keywords | Cytochrome P-450 / Drug-metabolizing enzyme / Phenobarbital / Metazolamede / Glutathione conjugation / Ciliary epithelium / Acetaminophen / 水晶体上皮細胞 |
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| Research Abstract |
Drug-metabolizing enzymes are also found in most extrahepatic tissues including the eye. Participation of such enzymes must be considered in understanding of bioavailability of medication and side effects accompanying drug therapy. Drugs which entered into cytoplasm are metabolized by these enzymes, which proceeds in two phases, namely phases I and II. During the phase I reaction, hydrophilic group(s) are introduced into the parent molecules. Conjugation enzyme(s) attack the hydrophilic group to form conjugated products (phase II reaction) which are excreted readily from cells. In this study we have studied both of the reactions in ocular tissues, and obtained the following results.
1) cytochrome P-450 content in the ciliary epithelium where activity of drug-metabolizing enzymes are highest in the eye was setermined. The content was only about 3% of that present in the liver, but was comparable to that in the lung which faces atomosphere.
2) Induction of cytochrome P-450 in the rabbit ey
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e was studied immunohistochemically after repeated phenobarbital injections. It was detected in the corneal epithelium, conjunctiva, and ciliary epithelium. when the injection was continued more than a week, the ciliary epithelium degenerated and cytochrome P-450 was no longer detected in the ciliary epithelium. In such cases cytochrome P-450 was detected in the lens. Protective role of drug-metabolizing enzymes in the ciliary epithelium for the lens was revealed.
3) Metazolamide, an antiglaucomatous agent, is conjugated spontaneously with glutathione at its physiological concentration. Glutathione S-transferase did not catalyze this reaction. The chemical structure of the conjugation product was determined. The product was degraded by gammaglutamyl transpeptidase.
4) Acetaminopminophen is reported to cause cataract in experimental animals in a certain condition. The toxicity of the drug and its derivatives to an established cell line of lens epithelum (Totl-86) was estimated by a surviving assay. Phenobarbital enhanced toxicity of acetaminophen slightly. Less
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