粒線體功能與藥物-研究員不可錯過的粒線體抑制劑總整理!－豐技生技's Blog

先前的文章曾經介紹過，粒線體是人體的能量工廠，參與了許多代謝反應 (延伸閱讀：●小知識分享● 千杯不醉就沒有酒精中毒的風險嗎?)，將我們食物攝取的營養轉化成人體可利用的能量。因此，如果粒線體功能異常，勢必會造成細胞死亡、影響正常的人體代謝功能。

Mitochondria -Stress in the powerhouse of the cell - The ...

(圖片來源: https://thescientificreporters.com/mitochondria-stress-in-the-powerhouse-of-the-cell/ )

目前有哪些藥物會抑制粒線體的功能呢? 讓我們一起看下去

利用粒線體的特殊功能，有許多臨床用藥會利用粒線體相關的訊息傳遞作為標的物，藉此增進或抑制人體的代謝系統。這些藥物主要調控的對象包括:

電子傳遞鏈
脂肪酸吸收與氧化 (脂肪酸代謝)
粒線體通透性轉變孔 (permeability transition pores, PTPs)
三磷酸腺苷酶 (ATPase)
離子通道與運輸蛋白 (ion channels and transporters)
心磷脂 (cardiolipin, CL)
mtDNA 以及蛋白質合成

影響粒線體功能的藥毒性

藥物對粒線體的毒性是醫藥研發的一大挑戰，研究發現有許多糖尿病用藥、抗癌藥、抗寄生蟲、抗病毒藥物、抗發炎藥物也都會影響到粒線體功能。因此，服用這類型藥物可能會傷害到人體的器官，特別是肝臟、腎臟、心臟或是骨骼肌的傷害。如果能了解這些藥物與粒線體之間的作用機制，將有助於降低因藥物毒性而產生嚴重副作用的風險。

在此我們整理了會影響粒線體功能的藥物，可以供臨床研究參考：

常見的粒線體抑制劑
1. 抑制電子傳遞鏈、解偶聯蛋白(uncoupler)、離子通道(ionophore)：
  rotenone, antimycin A, myxothiazole, metformin, cyanide, dinitrophenol, valinomycin, and nigericin
2. 調控粒線體通透性轉變孔 (PTP)：
  CsA, bongkrekic acid, betulinic acid, CD437, sangliferin, Ro 68-3400, atractyloside, and protoporhyrin IX
3. 調控粒線體鉀離子通道：
  diazoxide, pinacidil, nicorandil, cromakalim, glibenclamide, 5-HD, NS1619, NS004, CGS 7184, paxillline, IbTx, and ChTx
4. 抗氧化劑：
  MitoQ, SS31, Mito-CP, Mito-Tempo and MitoE
5. 抑制粒線體三磷酸腺苷酶 (ATPase)：
  oligomycin C, apoptolidin A, resveratrol, Bz-423, diindolyl-methane, aurovertin, PK11195, and R207910
影響粒線體功能的臨床用藥
1. 神經退化疾病：
  NSAIDs, minocycline, KB-R7943, dimebon, CsA, CoQ10, idebenone, lipoic acid, melatonin, vitamin E, nicotinamide, carnitine, resveratrol, sirtuits, FK 506, and deferoxamine
2. 癌症用藥：
  3-bromopyruvate, 2-deoxyglucose, methyl jasmonate, mannoheptulose, gossypol. ABT-737, antimycin A, A-385358, ABT-263, HA14-1, AT-101, obatoclax, isothiocyanates, arsenic trioxide, lonidamide, arsenites, GSAO, PK11195, clodronate, betulinic acid, CD437, Ro5-4684, a-TOS, tamoxifen, resveratrol, piceatannol, rhodamine-123, dichloroacetate, CAP-232/TLN-232, MJE3, vitamin K3, fialuridine, 2-methoxyestradiol, b-lapachone, menadione, STA-4783, and mangafodipir
3. 心血管疾病：
  CsA, sanglifehrin, NIM811, Debio025, bongkrekic acid, SSR180575, Ro5-4684; MitoSNO1, nitrite, mangafodipir, melatonin, edaravone, statins, UQ, Ro 68-3400, cariporide, propofol, MCI-186, pyruvate, diazoxide, minoxidil, pinacidil, a-lipolic acid, alda-1, etomoxir, perhexiline, ranolazine, trimetazidine, NAO, diazoside, 5-HD, glibenclamide, and BMS-191095
4. 抗寄生蟲藥物：
  ascofuranone, nafuredin, atovaquone, flutolanil, atpenin A5, and nafuredin-c (c-lactone derivative)
5. 糖尿病/肥胖與非酒精性脂肪肝：
  lipoic acid, acetyl-L-carnitine, thiazolidinediones, fibrates, thizolidinediones, L-carnitine, b-aminoisobutyric acid, resveratrol, SRT1720, vitamin E, trolox, ursodeoxycholic acid, and metmorfin
藥物引起的粒線體毒性
1. 常見的肝損傷藥物：
  acetaminophen, alpidem, disulfiram, SA, amineptine, amiodarone, buprenorphine, diclofenac, panadiplon, perhexiline, pirprofen, tamoxifen, VA, ibuprofen, nimesulide, SA, tacrine, tetracycline, troglitazone, didanosine, fialuridine, stavudine, and zidovudine
2. 心血管毒性：
  aminoglycoside and platinum chemotherapeutics, NRTIs, bupivacaine, lidocaine, thiazolidinediones, doxorubicin, daunorubicin, epirubicin, idarubicin, sorafenib, celecoxib, diclofenac, ibuprofen, indomethacin, mefenamic acid, meloxicam, naproxen, pirocicam, sulindac, atenolol, pioglitazone, and rosiglitazone
3. 腎毒性藥物：
  doxorubicin, cysplatin, gentamicin, CsA, ifosfamide, tenofovir, didanosine, indinavir, and atazanavir
4. 非類固醇消炎止痛藥 (NSAIDs)：
  celecoxib, ibuprofen, dicfolenac, indomethacin, nimesulide, mefenamic acid, meloxicam, naproxen, piroxicam, and sulidac
5. 粒線體鉀離子通道藥物的脫靶效應：
  diazoxide, pinacidil, glibenclamide, 5-HD, NS1619, CGS 7184, and paxilline
6. 麻醉藥：
  barbituranes, propofol, halothane, isoflurane, sevoflurane, bupivacaine, and articaine
7. 抗反轉錄病毒藥物：
  zidovudine, stavudine, lamivudine didanosine, zalcibatine, and abacavir
粒線體相關藥物傳遞系統：
1. Delocalized cations (e.g., rhodamine 123, MitoQ, MKT-077, TPP);
2. targeted peptides (e.g., szeto-schiller peptides);
3. vesicle delivery devices (e.g., dequalinum liposomes);
4. protein import pathway –MTS (e.g., covalent cross-linking, genetically MTS-fused proteins, combination of MTS);
5. and MITO-Porter