Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury.
Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury.
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DOI：
10.1093/toxsci/kfad015
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发表时间：
2023-03-20
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影响因子：
--
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中科院分区：
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氟氯西林是一种β-内酰胺类抗生素，与药物性肝损伤的发生率很高。虽然人类白细胞抗原-B*57：01的表达与易感性增加有关，但临床表型诱导的病理机制尚不清楚。不可逆的蛋白质修饰被认为是通过提供氟氯西林修饰的多肽来推动反应的，这些多肽由风险等位基因编码的蛋白质呈现给T细胞。在这项研究中，我们已经证明了氟氯西林可以与人原代肝细胞内的多种蛋白质结合，包括主要的肝细胞蛋白(血红蛋白和白蛋白)和线粒体蛋白。抑制膜转运体多药耐药相关蛋白2(MRP2)和P-糖蛋白(P-gp)似乎降低了共价结合水平。研究发现，氟氯西林作用于多种不同功能的蛋白质，包括接头蛋白(14-3-3)、具有催化活性的蛋白质(肝脏羧酸酯酶1、tRNA剪接核酸内切酶亚基Sen2、全反式视黄醇脱氢酶ADH1B、谷氨酸脱氢酶1线粒体、氨基磷酸合成酶[氨]线粒体)和转运蛋白(血红蛋白、白蛋白和UTP-葡萄糖-1-磷酸尿基转移酶)。这些氟氯西林修饰的胞内蛋白可能为肝细胞呈递人类白细胞抗原B*57：01提供潜在的新抗原源。更重要的是，与关键细胞蛋白的共价结合可能是导致氟氯西林诱导胆汁淤积的分子启动事件，可通过标识为PXD038581的ProteomeXchange获得数据。
Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver injury. Although expression of HLA-B*57:01 is associated with increased susceptibility, little is known of the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the provision of flucloxacillin-modified peptides that are presented to T-cells by the protein encoded by the risk allele. In this study, we have shown that flucloxacillin binds to multiple proteins within human primary hepatocytes, including major hepatocellular proteins (hemoglobin and albumin) and mitochondrial proteins. Inhibition of membrane transporters multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) appeared to reduce the levels of covalent binding. A diverse range of proteins with different functions was found to be targeted by flucloxacillin, including adaptor proteins (14-3-3), proteins with catalytic activities (liver carboxylesterase 1, tRNA-splicing endonuclease subunit Sen2, All-trans-retinol dehydrogenase ADH1B, Glutamate dehydrogenase 1 mitochondrial, Carbamoyl-phosphate synthase [ammonia] mitochondrial), and transporters (hemoglobin, albumin, and UTP-glucose-1-phosphate uridylyltransferase). These flucloxacillin-modified intracellular proteins could provide a potential source of neoantigens for HLA-B*57:01 presentation by hepatocytes. More importantly, covalent binding to critical cellular proteins could be the molecular initiating events that lead to flucloxacillin-induced cholestasis Data are available via ProteomeXchange with identifier PXD038581.
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影响因子：
14.9
作者：
Perez-Riverol Y;Bai J;Bandla C;García-Seisdedos D;Hewapathirana S;Kamatchinathan S;Kundu DJ;Prakash A;Frericks-Zipper A;Eisenacher M;Walzer M;Wang S;Brazma A;Vizcaíno JA
通讯作者：
Vizcaíno JA
影响因子：
4.6
作者：
Burban A;Sharanek A;Hüe R;Gay M;Routier S;Guillouzo A;Guguen-Guillouzo C
通讯作者：
Guguen-Guillouzo C
影响因子：
2.7
作者：
BALDO, BA;PHAM, NH;WEINER, J
通讯作者：
WEINER, J
影响因子：
6.1
作者：
Heslop JA;Rowe C;Walsh J;Sison-Young R;Jenkins R;Kamalian L;Kia R;Hay D;Jones RP;Malik HZ;Fenwick S;Chadwick AE;Mills J;Kitteringham NR;Goldring CE;Kevin Park B
通讯作者：
Kevin Park B
影响因子：
5.6
作者：
Bencharit, Sompop;Edwards, Carol C.;Redinbo, Matthew R.
通讯作者：
Redinbo, Matthew R.