| Project/Area Number |
13470463
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Periodontal dentistry
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| Research Institution | Okayama University |
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Principal Investigator |
NISHIMURA Fusanori Okayama University, Graduate School of Medicine and, Dentistry, Associate Professor, 大学院・医歯学総合研究科, 助教授 (80208222)
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| Co-Investigator(Kenkyū-buntansha) |
MAEDA Hiroshi Okayama University, Graduate School of Medicine and Dentistry, Instructor, 大学院・医歯学総合研究科, 助手 (00274001)
MYOKAI Fumio Okayama University, University Hospital of Medicine and Dentistry, Assistant Professor, 医学部・歯学部附属病院, 講師 (50263588)
大山 秀樹 岡山大学, 大学院・医歯学総合研究科, 助手 (90280685)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,400,000 (Direct Cost: ¥13,400,000)
Fiscal Year 2003: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2002: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 2001: ¥4,800,000 (Direct Cost: ¥4,800,000)
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| Keywords | drug-induced gingival overgrowth / lysosomal enzymes / cathepsin-L / deficient mice / anti-angiogenic effect / vascular endothelial growth factor / drug metabolizing enzyme / single nucleotide polymorphism / 薬物代謝 / フェニトイン / チトクロームP450 / CYP2C9 / CYP2C19 / Concentration(C) / Dose(D)ratio / Ca拮抗剤 / 抗てんかん薬 / 免疫抑制剤 / カテプシン / 欠損マウス / 表現型 / ニフェジピン / サイクロスポリン / I-cell病 |
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| Research Abstract |
Drug-induced gingival overgrowth develops as a side effect of certain medications. We previously reported that phenytoin and cyclosporine, well known drugs causing gingival overgrowth, suppressed cathepsin-L mRNA expression as well as its activity in gingival fibroblasts. Therefore, we first investigated the effects of nifedipine, another drug causing the disease, on lysosomal enzyme activity. As a result, nifedipine also suppressed cathepsin-L mRNA expression and its activity. Thus, all three drugs causing gingival overgrowth turned out to suppress cathepsin-L activity in vitro. Based on this observation, we investigated the in vivo effects of "complete loss of function" of cathepsin-L by using cathepsin-L deficient mice. Cathepsin-L deficient mice developed gingival overgrowth, while wild type mice did not. flistologically, overgrown gingival was characterized by a thickened epithelium as well as thickened connective tissue with elongated rete pegs into the connective tissue, phenotype extremely similar to that observed in human gingival overgrowth.
On the other hand, it is well known that cyclosporine exhibit anti-angiogenic effect, and that very few newly synthesized capillaries are observed in the lesion of drug-induced gingival overgrowth. We found that this was accompanied by the reduced expression of vascular endothelial growth factor via suppression of c jun N-terminal kinase activity by cyclosporine.
Finally, it is essential to keep particular blood drug concentration to develop gingival overgrowth. It has been reported that there exist several single nucleotide polymorphisms in the coding region of the enzyme responsible for metabolizing these drugs We found that particular genotype is closely associated with poor metabolic ability, and thus, we concluded that examining the genotype may be quite useful in predicting the disease susceptibility.
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