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第38巻 第2号 >

ビスホスホネートと2価金属イオンとの拮抗によるアルカリ性ホスファターゼ活性の阻害

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Title: ビスホスホネートと2価金属イオンとの拮抗によるアルカリ性ホスファターゼ活性の阻害
Other Titles: Inhibition of alkaline phosphatase activity by competition between bisphosphonates and divalent metal ions
Authors: 三上, 翔1 Browse this author
鈴木, 邦明2 Browse this author →KAKEN DB
島田, 英知3 Browse this author
吉村, 善隆4 Browse this author →KAKEN DB
南川, 元5 Browse this author
山崎, 裕6 Browse this author →KAKEN DB
Authors(alt): Mikami, Sho1
Suzuki, Kuniaki2
Shimada, Hidetomo3
Yoshimura, Yoshitaka4
Minamikawa, Hajime5
Yamazaki, Yutaka6
Keywords: ビスホスホネート
アルカリ性ホスファターゼ
パラニトロフェニルリン酸
ピロリン酸
2価金属イオン
bisphosphonate
alkaline phosphatase
p-nitrophenylphosphate
pyrophosphate
divalent metal ions
Issue Date: Mar-2018
Publisher: 北海道歯学会
Journal Title: 北海道歯学雑誌
Volume: 38
Issue: 2
Start Page: 211
End Page: 218
Abstract: ビスホスホネート(BP)によるALP活性抑制の報告があるが,その機構は不明な点が多い.そこで,ヒト組織非特異型ALP(骨型,肝臓型),及び組織特異型ALP(胎盤型)とマウス由来骨芽細胞様細胞であるMC3T3-E1細胞のALPに対する,窒素非含有型のclodronate,窒素含有型のrisedronate及びalendronateによるALP活性の阻害機構を検討した.Mg,Zn及びCa存在下の活性を,それぞれ,Mg-ALP,Zn-ALP及びCa-ALPとし,基質としてパラニトロフェニルリン酸(p NPP)あるいは無機ピロリン酸(PPi)を使用した.p NPPを基質とした骨型及び肝臓型の各ALP活性はclodronate,risedronate及びalendronateの濃度に依存して抑制された.Mg-ALPでは,各BPとMgとの拮抗が見られたが,Zn-及びCa-ALP活性におけるBPとZn及びCaとの拮抗は,Mg-ALPほど顕著ではなかった.また,clodronateと比較してrisedronate及びalendronateのほうが強いMg-ALP抑制作用を示し,阻害作用は窒素非含有型と比較して窒素含有型BPのほうが強いことが示唆された. PPiを基質とすると,clodronateはMC3T3-E1及びヒト胎盤型ALPのCa-ALP活性を,Caと拮抗して濃度依存性に抑制した.P-C-P結合を持つBPがP-O-P結合を持つ基質と拮抗する可能性を考えて,骨型及び肝臓型ALPを使用して,Mg-,Zn-及びCa-ALP活性のp NPP濃度依存性に対するclodronate,risedronate及びalendronateの影響を検討した.BPは濃度に依存して最大活性を抑制したがp NPPによる50%活性化濃度には顕著な影響を与えず,BPはALPの基質であるp NPPとは拮抗しないことを示唆した.以上の結果は,BPはALPの種類,基質,活性化する2価金属の種類に関係なく,2価金属イオンとの拮抗によりALP活性を阻害し,その作用は窒素含有型が非含有型と比較して強いことを示唆した.
Recent investigations have demonstrated that bisphosphonate (BP) inhibits ALP activities, but there are still many points that remain uncovered. We tested the inhibitions of human bone, placental, and liver type ALP activity in the presence of Mg, Zn and Ca (as Mg, Zn, and Ca-ALP respectively), with paranitrophenyl phosphate (p NPP) or inorganic pyrophosphate (PPi) as substrates, using various BPs: non- nitrogen-containing BP clodronate and nitrogen-containing BP risedronate and alendronate for inhibitors. Using p NPP as a substrate, the relationship between the effects of clodronate, risedronate or alendronate on bone or liver Mg, Zn and Ca-ALP activities, and the concentrations of coexisting Mg, Zn and Ca were examined. Mg, Zn, and Ca-ALP activities of both isozymes decreased to the concentration dependency of each BP ; this was required as higher concentrations of BPs as the coexisting Mg concentration was higher for the suppression of Mg-ALP activity by BPs. In addition, risedronate and alendronate showed stronger Mg-ALP inhibitory action compared with clodronate. These results suggest that BP inhibits human bone and liver Mg-ALP activity competitively with Mg. Also, the strength of the inhibition by nitrogen-containing BPs are stronger than those of non-nitrogen-containing BPs. For Zn and Ca-ALP activities, BPs also showed a tendency of competition with Zn or Ca, but not as significant as Mg. Clodronate suppressed the Ca-ALP activities of MC3T3-E1 and human placental ALP using PPi as substrates, to the concentration dependency competitively with Ca. Considering the possibility that BP with a P-C-P structure might compete with the substrates containing a P-O-P structure, we measured the effects of clodronate, risedronate, and alendronate on p NPP concentration dependency of human bone and liver Mg, Zn and Ca-ALP activities. BPs inhibited the maximum activity depending on the concentration, but did not significantly affect the 50 % activtity concentration by p NPP. This suggests that BPs do not compete with the substrate of ALP, p NPP. These results suggest that BP inhibits ALP activity by competition with bivalent metal, regardless of the type of ALP, substrate, and the type of bivalent metal for the activation. In addition, its action of nitrogen-containing BP is stronger than non-nitrogen-containing BP.
Type: article
URI: http://hdl.handle.net/2115/68807
Appears in Collections:北海道歯学雑誌 = Hokkaido Journal of Dental Science > 第38巻 第2号

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