Potential repurposing of known drugs as potent bacterial β-glucuronidase inhibitors.
Potential repurposing of known drugs as potent bacterial β-glucuronidase inhibitors.
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DOI：
10.1177/1087057112444927
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发表时间：
2012-08
影响因子：
--
通讯作者：
Scott JE
中科院分区：
文献类型：
--
作者：
Ahmad S;Hughes MA;Yeh LA;Scott JE
化疗伊立替康的活性代谢物SN-38通过葡萄糖醛酸化作用解毒，然后排泄到胃肠道。肠道细菌利用β-葡萄糖醛酸苷酶(GUS)将葡萄糖醛酸化的代谢物转化回有毒的SN-38，导致虚弱的腹泻。抑制GUS活性可能会减轻伊立替康的副作用。在这项研究中，我们试图确定是否有任何已知的药物具有GUS抑制活性。我们使用纯化的细菌GU，通过无细胞生化酶试验筛选了FDA批准的药物文库。经过分选，确定了5种药物对纯化的细菌GUS有抑制作用。其中3种是单胺氧化酶抑制剂烟酰胺、异烟肼和苯乙肼，对GUS的平均IC50值分别为71、128和2,300 nM。三环类抗抑郁药阿莫沙平(IC_(50)=388 nM)和抗疟药甲氟喹(IC_(50)=1.2μM)也有活性。烟酰胺、异烟肼和阿莫沙平对纯化的哺乳动物GUS没有明显的抑制活性，但在活的完整大肠杆菌的细胞实验中显示出很强的抑制内源性GUS活性的活性，其IC50值分别为17、336和119 nM。因此，烟酰胺、异烟肼和阿莫沙平有可能被重新用作治疗药物，以减少伊立替康化疗引起的腹泻，并值得进一步研究这种用途。
The active metabolite of the chemotherapeutic irinotecan, SN-38, is detoxified through glucuronidation and then excreted into the gastrointestinal tract. Intestinal bacteria convert the glucuronidated metabolite back to the toxic SN-38 using β-glucuronidase (GUS), resulting in debilitating diarrhea. Inhibiting GUS activity may relieve this side-effect of irinotecan. In this study, we sought to determine whether any known drugs have GUS inhibitory activity. We screened a library of FDA-approved drugs with a cell-free biochemical enzyme assay using purified bacterial GUS. After triage, five drugs were confirmed to inhibit purified bacterial GUS. Three of these were the monoamine oxidase inhibitors nialamide, isocarboxazid and phenelzine with average IC50 values for inhibiting GUS of 71, 128 and 2,300 nM. The tricyclic antidepressant amoxapine (IC50 = 388 nM) and the antimalarial mefloquine (IC50 = 1.2 μM) also had activity. Nialamide, isocarboxazid and amoxapine had no significant activity against purified mammalian GUS, but showed potent activity for inhibiting endogenous GUS activity in a cell-based assay using living intact E. coli with average IC50 values of 17, 336 and 119 nM, respectively. Thus, nialamide, isocarboxazid, and amoxapine have potential to be repurposed as therapeutics to reduce diarrhea associated with irinotecan chemotherapy and warrant further investigation for this use.
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影响因子：
4.9
作者：
Stein, Alexander;Voigt, Wieland;Jordan, Karin
通讯作者：
Jordan, Karin
DOI：
10.1126/science.1191175
发表时间：
2010-11-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wallace BD;Wang H;Lane KT;Scott JE;Orans J;Koo JS;Venkatesh M;Jobin C;Yeh LA;Mani S;Redinbo MR
通讯作者：
Redinbo MR
DOI：
10.1111/j.1476-5381.1961.tb01118.x
发表时间：
1961-01-01
期刊：
BRITISH JOURNAL OF PHARMACOLOGY AND CHEMOTHERAPY
影响因子：
--
作者：
MAXWELL, DR;TAYLOR, EM;GRAY, WR
通讯作者：
GRAY, WR
影响因子：
5.8
作者：
Ulus, IH;Maher, TJ;Wurtman, RJ
通讯作者：
Wurtman, RJ
影响因子：
3
作者：
Kurita, Akinobu;Kado, Shoichi;Yokokura, Teruo
通讯作者：
Yokokura, Teruo