Regulation of Human Endogenous Metabolites by Drug Transporters and Drug Metabolizing Enzymes: An Analysis of Targeted SNP-Metabolite Associations.
Regulation of Human Endogenous Metabolites by Drug Transporters and Drug Metabolizing Enzymes: An Analysis of Targeted SNP-Metabolite Associations.
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DOI：
10.3390/metabo13020171
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发表时间：
2023-01-24
期刊：
影响因子：
4.1
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中科院分区：
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--
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药物转运蛋白和药物代谢酶主要以其在小分子药物的吸收、分布、代谢和排泄（ADME）中的作用而闻名，但它们在处理内源性代谢物中也起关键作用。最近的跨组织共表达网络分析揭示了参与内源性代谢的多特异性、寡特异性和单特异性转运蛋白和酶的“遥感和信号网络”。这包括来自参与ADME的家族的许多蛋白质（例如，SLC22、SLC0、ABCC、UGT）。聚焦于肠-肝-肾轴，我们通过将这些基因中的SNP与数千种小的极性生物活性代谢物的循环水平相关联，确定了可能受约1000种蛋白质网络调节的内源性代谢物，这些代谢物包括游离脂肪酸，类花生酸，胆汁酸和其他信号代谢物，这些代谢物部分通过G蛋白偶联受体（GPCR），核受体和激酶起作用。我们确定了77个基因组位点与7236个独特的代谢产物。这包括与多个不同位点相关的代谢物，表明特定代谢物的多个基因（包括药物转运蛋白和药物代谢酶）之间的协调调节。我们分析了现有的药物基因组学数据，并注意到与内源性代谢物处理有关的SNP（例如，SLCO 1B 1中的rs 4149056）也影响药物ADME。总体结果支持存在的密切关系，通过相互作用与信号代谢物，药物转运蛋白和药物代谢酶的遥感和信号网络的一部分，并与GPCR和核受体之间。这些分析强调了在遥感和信号网络和ADME蛋白质网络的接口处药物代谢物相互作用的潜力。
Drug transporters and drug-metabolizing enzymes are primarily known for their role in the absorption, distribution, metabolism, and excretion (ADME) of small molecule drugs, but they also play a key role in handling endogenous metabolites. Recent cross-tissue co-expression network analyses have revealed a “Remote Sensing and Signaling Network” of multispecific, oligo-specific, and monospecific transporters and enzymes involved in endogenous metabolism. This includes many proteins from families involved in ADME (e.g., SLC22, SLCO, ABCC, CYP, UGT). Focusing on the gut−liver−kidney axis, we identified the endogenous metabolites potentially regulated by this network of ~1000 proteins by associating SNPs in these genes with the circulating levels of thousands of small, polar, bioactive metabolites, including free fatty acids, eicosanoids, bile acids, and other signaling metabolites that act in part via G-protein coupled receptors (GPCRs), nuclear receptors, and kinases. We identified 77 genomic loci associated with 7236 unique metabolites. This included metabolites that were associated with multiple, distinct loci, indicating coordinated regulation between multiple genes (including drug transporters and drug-metabolizing enzymes) of specific metabolites. We analyzed existing pharmacogenomic data and noted SNPs implicated in endogenous metabolite handling (e.g., rs4149056 in SLCO1B1) also affecting drug ADME. The overall results support the existence of close relationships, via interactions with signaling metabolites, between drug transporters and drug-metabolizing enzymes that are part of the Remote Sensing and Signaling Network, and with GPCRs and nuclear receptors. These analyses highlight the potential for drug−metabolite interactions at the interfaces of the Remote Sensing and Signaling Network and the ADME protein network.
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影响因子：
25
作者：
Breen G;Li Q;Roth BL;O'Donnell P;Didriksen M;Dolmetsch R;O'Reilly PF;Gaspar HA;Manji H;Huebel C;Kelsoe JR;Malhotra D;Bertolino A;Posthuma D;Sklar P;Kapur S;Sullivan PF;Collier DA;Edenberg HJ
通讯作者：
Edenberg HJ
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
5.6
作者：
Engelhart, Darcy C.;Azad, Priti;Nigam, Sanjay K.
通讯作者：
Nigam, Sanjay K.
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
4.8
作者：
Bush, Kevin T.;Wu, Wei;Nigam, Sanjay K.
通讯作者：
Nigam, Sanjay K.