Intestine is responsible for the biotransformation of many orally-exposed chemicals.The constitutive androstane receptor(CAR/Nr1i3) is known to up-regulate many genes encoding drugmetabolizing enzymes and transporters...Intestine is responsible for the biotransformation of many orally-exposed chemicals.The constitutive androstane receptor(CAR/Nr1i3) is known to up-regulate many genes encoding drugmetabolizing enzymes and transporters(drug-processing genes/DPGs) in liver,but less is known regarding its effect in intestine.Sixty-day-old wild-type and Car / mice were administered the CARligand TCPOBOP or vehicle once daily for 4 days.In wild-type mice,Car m RNA was down-regulated by TCPOBOP in liver and duodenum.Car / mice had altered basal intestinal expression of many DPGs in a section-specific manner.Consistent with the liver data(Aleksunes and Klaassen,2012),TCPOBOP upregulated many DPGs(Cyp2b10,Cyp3a11,Aldh1a1,Aldh1a7,Gsta1,Gsta4,Gstm1-m4,Gstt1,Ugt1a1,Ugt2b34,Ugt2b36,and Mrp2–4) in specific sections of small intestine in a CAR-dependent manner.However,the m RNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine.Interestingly,many known CAR-target genes were highest expressed in colon where CAR is minimally expressed,suggesting that additional regulators are involved in regulating their expression.In conclusion,CAR regulates the basal expression of many DPGs in intestine,and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine,pharmacological activation of CAR in liver and intestine are not identical.展开更多
基金supported by U.S. National Institute of Health R-01 grants ES019487,ES025708,and GM11138start-up funds from University of Washington Center for Ecogenetics and Environmental Health (P30ES007033)
文摘Intestine is responsible for the biotransformation of many orally-exposed chemicals.The constitutive androstane receptor(CAR/Nr1i3) is known to up-regulate many genes encoding drugmetabolizing enzymes and transporters(drug-processing genes/DPGs) in liver,but less is known regarding its effect in intestine.Sixty-day-old wild-type and Car / mice were administered the CARligand TCPOBOP or vehicle once daily for 4 days.In wild-type mice,Car m RNA was down-regulated by TCPOBOP in liver and duodenum.Car / mice had altered basal intestinal expression of many DPGs in a section-specific manner.Consistent with the liver data(Aleksunes and Klaassen,2012),TCPOBOP upregulated many DPGs(Cyp2b10,Cyp3a11,Aldh1a1,Aldh1a7,Gsta1,Gsta4,Gstm1-m4,Gstt1,Ugt1a1,Ugt2b34,Ugt2b36,and Mrp2–4) in specific sections of small intestine in a CAR-dependent manner.However,the m RNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine.Interestingly,many known CAR-target genes were highest expressed in colon where CAR is minimally expressed,suggesting that additional regulators are involved in regulating their expression.In conclusion,CAR regulates the basal expression of many DPGs in intestine,and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine,pharmacological activation of CAR in liver and intestine are not identical.
