Rifampin modulation of xeno- and endobiotic conjugating enzyme mRNA expression and associated microRNAs in human hepatocytes.
Rifampin modulation of xeno- and endobiotic conjugating enzyme mRNA expression and associated microRNAs in human hepatocytes.
复制标题
利福平调节人肝细胞中的外源性和内生性缀合酶 mRNA 表达及相关 microRNA。
DOI：
10.1002/prp2.386
复制
发表时间：
2018-04
影响因子：
2.6
通讯作者：
Skaar TC
中科院分区：
文献类型：
--
作者：
Gufford BT;Robarge JD;Eadon MT;Gao H;Lin H;Liu Y;Desta Z;Skaar TC
利福平是多种药物代谢酶和转运蛋白的多效性诱导剂。这项工作利用了一种全球性方法来评价利福平对结合酶基因表达的影响，并与人类异种和内生代谢相关。用利福平（10 μmol/L，24小时）处理7例受试者的原代人肝细胞。使用RNA-seq文库构建、EZBead制备和NextGen测序的标准方法测量UDP-葡萄糖醛酸基转移酶UGT、磺酰转移酶SULT、N乙酰转移酶NAT和谷胱甘肽-S-转移酶GST mRNA表达，并与溶剂对照（0.01% MeOH）进行比较。利福平诱导（>1.25倍）13个临床重要的II期药物代谢基因的mRNA表达，并抑制（>1.25倍）3个基因的表达（P < .05）。利福平诱导的miRNA表达变化与mRNA变化相关，并鉴定了可能调节结合酶表达的miRNA。利福平对NAT 2基因表达的抑制作用最强（1.3倍），而对UGT 1A 4和UGT 1A 1基因的诱导作用最强（分别为7.9倍和4.8倍）。使用基于生理学的药代动力学建模（PBPK）模拟利福平诱导CYP 3A 4和UGT 1A 4介导的咪达唑仑代谢的临床结果。评价单独UGT 1A 4诱导的模拟预测咪达唑仑N-葡萄糖醛酸苷暴露量增加（约4倍），母体咪达唑仑暴露量降低最小（约10%）。考虑CYP 3A 4和UGT 1A 4同时诱导的模拟预测母体咪达唑仑暴露量降低约10倍，咪达唑仑N-葡糖苷酸代谢产物暴露量仅降低约2倍。这些数据揭示了利福平对人类结合酶转录组的不同影响，以及与miRNA的潜在关联，这些miRNA构成了未来机制研究的基础，以阐明结合酶调控元件的相互作用。
Rifampin is a pleiotropic inducer of multiple drug metabolizing enzymes and transporters. This work utilized a global approach to evaluate rifampin effects on conjugating enzyme gene expression with relevance to human xeno‐ and endo‐biotic metabolism. Primary human hepatocytes from 7 subjects were treated with rifampin (10 μmol/L, 24 hours). Standard methods for RNA‐seq library construction, EZBead preparation, and NextGen sequencing were used to measure UDP‐glucuronosyl transferase UGT, sulfonyltransferase SULT, N acetyltransferase NAT, and glutathione‐S‐transferase GST mRNA expression compared to vehicle control (0.01% MeOH). Rifampin‐induced (>1.25‐fold) mRNA expression of 13 clinically important phase II drug metabolizing genes and repressed (>1.25‐fold) the expression of 3 genes (P < .05). Rifampin‐induced miRNA expression changes correlated with mRNA changes and miRNAs were identified that may modulate conjugating enzyme expression. NAT2 gene expression was most strongly repressed (1.3‐fold) by rifampin while UGT1A4 and UGT1A1 genes were most strongly induced (7.9‐ and 4.8‐fold, respectively). Physiologically based pharmacokinetic modeling (PBPK) was used to simulate the clinical consequences of rifampin induction of CYP3A4‐ and UGT1A4‐mediated midazolam metabolism. Simulations evaluating isolated UGT1A4 induction predicted increased midazolam N‐glucuronide exposure (~4‐fold) with minimal reductions in parent midazolam exposure (~10%). Simulations accounting for simultaneous induction of both CYP3A4 and UGT1A4 predicted a ~10‐fold decrease in parent midazolam exposure with only a ~2‐fold decrease in midazolam N‐glucuronide metabolite exposure. These data reveal differential effects of rifampin on the human conjugating enzyme transcriptome and potential associations with miRNAs that form the basis for future mechanistic studies to elucidate the interplay of conjugating enzyme regulatory elements.
登录
查看更多内容
影响因子：
5.6
作者：
Benson EA;Eadon MT;Desta Z;Liu Y;Lin H;Burgess KS;Segar MW;Gaedigk A;Skaar TC
通讯作者：
Skaar TC
影响因子：
5.9
作者：
Dluzen DF;Lazarus P
通讯作者：
Lazarus P
影响因子：
3.8
作者：
Endo Y;Yamashita H;Takahashi S;Sato S;Yoshimoto N;Asano T;Hato Y;Dong Y;Fujii Y;Toyama T
通讯作者：
Toyama T
DOI：
10.1124/jpet.113.210658
发表时间：
2014-03-01
影响因子：
3.5
作者：
Dluzen, Douglas F.;Sun, Dongxiao;Lazarus, Philip
通讯作者：
Lazarus, Philip
DOI：
10.1152/ajpgi.00258.2004
发表时间：
2005-01-01
影响因子：
4.5
作者：
Li, TG;Chiang, JYL
通讯作者：
Chiang, JYL