Exploring the Use of Serum-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides
Exploring the Use of Serum-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides
复制标题
DOI：
10.1002/cpt.2244
复制
发表时间：
2021-04-18
影响因子：
6.7
通讯作者：
Rowland, Andrew
中科院分区：
文献类型：
--
作者：
Rodrigues, A. David;van Dyk, Madele;Rowland, Andrew
采用一种新的两步法从少量库存血清样品中制备肝源性小细胞外囊泡（sEVs），作为液体活检来研究细胞色素P450的诱导（CYP 3A 4、CYP 3A 5和CYP 2D 6）和有机阴离子转运多肽健康男性受试者在妊娠期间（非妊娠（T0）、妊娠早期、妊娠中期和妊娠晚期（T3）女性;各N = 3）和利福平（RIF）给药后的OATP 1B 1和OATP 1B 3。蛋白质组学分析显示诱导RIF 300 mg × 7天后sEV CYP 3A 4的（平均增加倍数，90%置信区间）（3.5，95% CI = 2.5-4.5，N = 4，P = 0.029）和600 mg × 14天（3.7，95% CI = 2.1-6.0，N = 5，P = 0.018）与相同受试者的平均口服咪达唑仑血药浓度-时间曲线下面积（AUC）比值一致（0.28，95%CI = 0.22-0.34，P < 0.0001; 0.17，95%CI = 0.13-0.22，P < 0.0001）。与CYP 3A 4相比，肝脏sEV CYP 3A 5蛋白（受试者基因型CYP 3A 5 *1/*3）被弱诱导（
Liver-derived small extracellular vesicles (sEVs), prepared from small sets of banked serum samples using a novel two-step protocol, were deployed as liquid biopsy to study the induction of cytochromes P450 (CYP3A4, CYP3A5, and CYP2D6) and organic anion transporting polypeptides (OATP1B1 and OATP1B3) during pregnancy (nonpregnant (T0), first, second, and third (T3) trimester women; N = 3 each) and after administration of rifampicin (RIF) to healthy male subjects. Proteomic analysis revealed induction (mean fold-increase, 90% confidence interval) of sEV CYP3A4 after RIF 300 mg x 7 days (3.5, 95% CI = 2.5-4.5, N = 4, P = 0.029) and 600 mg x 14 days (3.7, 95% CI = 2.1-6.0, N = 5, P = 0.018) consistent with the mean oral midazolam area under the plasma concentration time curve (AUC) ratio in the same subjects (0.28, 95% CI = 0.22-0.34, P < 0.0001; and 0.17, 95% CI = 0.13-0.22, P < 0.0001). Compared with CYP3A4, liver sEV CYP3A5 protein (subjects genotyped CYP3A5*1/*3) was weakly induced (