分子毒理通路发现者PCR芯片
分子毒理通路发现者PCR芯片可用于研究与13个被药物毒性激活的生物学通路中的370个关键基因的表达。在药物处理后的细胞系或组织（肝脏）中进行这些基因的表达情况的检测，可以找到该药物诱导的毒理反应 ，包括编码电子转运链以及氧化磷酸化复合物组成蛋白的基因。了解这些机制可以帮助我们对药物的化学结构进行修改来避免药物的毒性反应，而不是完全地否定某个对疾病有治疗或者预防作用的药物。这张芯片上所有的毒性反应通路，可以是独立的也可以是相互关联的。例如，β-氧化导致脂肪变性，线粒体能量代谢解偶联导致细胞的凋亡和坏死。影响活性氧代谢或细胞的氧化还原反应的药物会引起氧化应急和抗氧化系统的相应。这些反应性的药物可能在极端情况下通过活化DNA损伤信号以及DNA修复，细胞凋亡和坏死的信号通路，直接损伤DNA或者抑制DNA的修复。干扰蛋白质合成的过程，会引起内质网应激，激活未折叠的蛋白放映，上调热休克蛋白和伴侣基因的表达。细胞色素P450以及其他第一阶段的药物代谢酶会在药物抑制其化学修饰活性的情况下表达量升高。在更为严重的情况下药物抑制脂肪酸和脂质代谢，包括胆汁淤积，脂质贮积症以及磷脂质病。药物对免疫系统细胞的毒性反应可以引起免疫抑制或者免疫毒性。利用实时定量PCR，研究者可以方便并且可信地对药物的毒理反应通路相关的基因进行同时检测。 Apoptosis: ABL1, AKT1, APAF1, BAD, BAK1, BAX, BCL2, BCL2L1 (BCL-X), BCL2L11, BID, BIRC3 (c-IAP1), CASP1 (ICE), CASP3, CASP7, CASP8 (FLICE), CASP9, CD40 (TNFRSF5), CD40LG (TNFSF5), CFLAR (CASPER), FADD, FAS (TNFRSF6), FASLG (TNFSF6), GADD45A, MCL1, TNF, TNFRSF10A, TNFRSF10B (DR5), TNFRSF1A, TNFSF10 (TRAIL), TP53, XIAP. Necrosis: ATP6V1G2, BMF, CCDC103, CD300LD, CLEC18A, COMMD4, CYLD, DEFB1, DPYSL4, EIF5B, FOXI1, GALNT5, GRB2, HOXA3, HSPBAP1, JPH3, KCNIP1, MAG, NUDT13, OR10J3, PARP2, PVR, RAB25, S100A7A, SPATA2, SYCP2, TMEM57, TNFAIP8L1, TNFRSF1A, TXNL4B. DNA Damage & Repair: APEX1, ATM, ATR, BRCA1, BRCA2, CDKN1A (p21CIP1/WAF1), CHEK1, CHEK2 (RAD53), DDIT3 (GADD153/CHOP), ERCC1, ERCC2 (XPD), ERCC3 (XPB), ERCC5, ERCC6, GADD45A, LIG4, MDM2, MGMT (AGT), MLH1, MSH2, OGG1, PARP1 (ADPRT1), PCNA, PRKDC, RAD51, TP53, XPA, XPC, XRCC1, XRCC5. Mitochondrial Energy Metabolism: ACLY, ACO1, ACO2, COX6B1, COX8A, CS, CYC1, DLD, DLST, FH, IDH1, IDH2, IDH3A, IDH3B, IDH3G, MDH1, MDH1B, MDH2, OGDH, SDHA, SDHB, SDHC, SDHD, SUCLA2, SUCLG1, SUCLG2, UCP1, UCP2, UCP3. Fatty Acid Metabolism (ß-Oxidation): ACAA1, ACAA2, ACAD11, ACAD9, ACADL, ACADM, ACADS, ACADSB, ACADVL, ACAT1, ACAT2, ACOT1, ACOT12, ACOT6, ACOT7, ACOT8, ACOT9, ACOX1, ACOX2, ACOX3, BDH2, CPT1A, CPT1B, CPT2, CRAT, CROT, DECR1, ECHS1, EHHADH, GCDH, HADHA. Oxidative Stress & Antioxidant Response: AASS, CAT, CTSB, DHCR24, DUOX1, DUOX2, EPX, GPX1, GPX2, GPX3, GPX4, GPX5, GPX6, GPX7, IDH1, MPO, NQO1, NUDT1, NUDT15, PPP1R15B, PRDX1, PRDX2, PRDX6 (AOP2), SOD1, TPO, TXNIP, TXNRD2, UCP3. Heat Shock Response: CRYAA, CRYAB, DNAJA1, DNAJA2, DNAJA3, DNAJB1, DNAJB6, DNAJC3, DNAJC5, DNAJC6, HSF1 (TCF5), HSF2, HSP90AA1, HSP90AB1, HSP90B1 (TRA1), HSPA1A, HSPA1B, HSPA1L, HSPA2, HSPA4 (HSP70), HSPA5 (GRP78), HSPA8, HSPA9, HSPB1 (HSP27), HSPB2, HSPB6, HSPB8, HSPD1, HSPE1, HSPH1 (HSP105), TCP1. ER Stress & Unfolded Protein Response: AMFR, ATF4, ATF6, BAX, DDIT3, DERL1, EDEM1, EDEM3, EIF2AK3, ERN2, ERO1L, ERO1LB, FBXO6, GADD45A, HERPUD1, HTRA2, HTRA4, MBTPS1, MBTPS2, NPLOC4, NUCB1, OS9, PFDN5, SEC62, SEL1L, SELS, SERP1, SYVN1, UBE2G2, UBE2J2, UBXN4, VCP, XBP1. Cytochrome P450s & Phase I Drug Metabolism: CYP1A1, CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP2E1, CYP3A4, ESD, FMO2, FMO3, FMO4, FMO5, MAOA, MAOB. Steatosis: ACACA, ADK, ALDH2, AQP4, CD36, COMT, CYP2E1, CYP7B1, DNM1, ENO1, FAS, FASN, GPD1, HAAO, HADHB, KHK, LMNA, LPL, LY6D, MAPK8 (JNK1), MTTP, PCCA, PNPLA3, PPARA, RETN, SCD, SREBF1, SYT1, TFF3, VCP. Cholestasis: ABCB1, ABCB4, ABCC1 (MRP1), ABCC2 (MRP2), ABCC3 (MRP3), APOE, ATP8B1, CYP3A4, CYP7A1, DLAT, ESR1 (ERa), HLA-DRB1, ICAM1, IL10, IL1B, IL2, IL6, JAG1, MPO, NR1H4, NUP210, OSTALPHA, OSTBETA, PDYN, RDX, SLC10A1, TGFB1, TNF. Phospholipidosis: ABCB1 (MDR1), ALDH1A1, ASAH1, ASNS, CES2, CTSB, EPHX1, FABP1, FXC1 (TIMM10B), GSTM4, HPN, INHBE, LSS, MANBA, MLX, MRPS18B, NR0B2, POR, S100A8, SC4MOL, SERPINA3, SLC2A3, SLCO1A2, SMPD1, STBD1, TAGLN, UGT1A1, UGT2A1, UGT2B4, WIPI1. Immunotoxicity: ADH1C, AHR, AHSG, ALB, APOA5, APOF, C3, C9, CASP3, CD19, CD4, CD44, CD80, CD86, CD8A, CTSE, CYP1A1, CYP3A4, CYP3A4, EP300, F2, FABP1, FAS, GPT, GSTA3, HPX, HRG, HSPA5, IFNA1, IFNG, IL10, IL13, IL1A, IL1B, IL2, IL4, IL5, IL6, ITGAX, KLF1, LYZ, LYZ, METAP2, MKI67, NFKB1, NR5A2, PON1, POU3F3, PTGS2 (COX2), PTPRC, SOD1, TNF, TRIM10, UBQLN2. |
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