Neonatal activation of Pxr results in persistent altered expression of DMEs in adult mice

OBJECTIVE To demonstrate the long-or short-term impacts of neonatal Pxr(pregnane X receptor) agonists exposureon DMEs(drug metabolism enzymes) expression in adulthood.METHODS C57 BL/6 mice(day 5,postnatal) were injected with different doses(0,50,100,150,200 mg·kg^(-1) ·d^(-1),constitutive 4 d) of PCN(pregnenolone-16 a-carbonitrile).Mice at different ages(day 5,10,15,25,postna.tal) were administrated with 200 mg·kg^(-1)·d^(-1) PCN in constitutive 4 d.All mice were sacrificed at day 60 after birth.Liver samples were collected for detecting the expression of Pxr target genes.RESULTS Compared with vehicle group,the significant inductions of Cyp2 b10,Cyp3a11 and Pxrwere observed in high dose groups(150,200 mg·kg^(-1) ·d^(-1),5-8 d after birth) both in male and female mice(n=4-9/group,P<0.05).Furthermore,high dose groups(200 mg·kg^(-1)·d^(-1),5-8 d after birth) were found to have higher mRNA expression levels of Cyp2a4,Ugt1a1,Abcc4,and Oatpla4 in female mice,while Papss2 in male mice compared with vehicle groups(n= 4-9/group,P<0.05).Interestingly,a decreased mRNA expression of Sult2a1 was identified in 200(5-8 d) groups(n=4-9/group,P<0.05).Consistent with these results,the protein expression of Cyp3a11 was only increased in 200(5-8 d) groups compared with the vehicle groups(n=3/group,P<0.05).Importantly,the persistent impacts on DMEs only occurred in day 5 and day 25 treatment groups,not day 10 and day 15 groups(n=4/group).CONCLUSION Neonatal Pxr activation has a long-term effect on the expression of DMEs in C57BL/6 mice.Dose and treatment exposure time are two key factors involved in this permanent alteration procedure.