, insertion into pIRESneo (BD Biosciences ? Clontech) digested with EcoRI/BamHI. Human CYP24 promoter deletions were obtained by PCR (Pfu polymerase ; Promega Corp.) using CYP24 forward 18-mer oligonucleotide primers (?1) with an overhanging SalI site immediately upstream of the 5?-most base of the deletion construct; a common 3? primer, TGCATTTATGGAGACAGA (CYP24 ?39 to ?22); and the human CYP24 (?1,250 to +99) pBLCAT3 plasmid as a template (a gift from PCR products were then digested by SacI and subcloned in SacI/SmaI?linearized pGL3basic vector (Promega Corp.) to produce ?1,200-LUC, ?326-LUC, and ?144-LUC constructs. pGL3tkLUC plasmid was obtained by ligation of the HindIII/BglII tk-SEAP vector fragment (BD Biosciences ? Clontech), corresponding to the minimal 147nt long tk promoter, into the HindIII/BglII?linearized pGL3basic vector. Oligonucleotides corresponding to the individual CYP2B6 NR1 (55), CYP24 site 3 (?316 to ?291), and VDREs (VDRE-II, ?294 to ?274, and VDRE-I, ?174 to ?151) (37) were synthesized with BamHI and BglII ends, annealed, and ligated, and 3 copies were subcloned into the BamHI/BglII?digested pGL3tk. The resulting (NR1)3-tkLUC, (site 3)3-tkLUC, (VDRE-II)3-tkLUC, and (VDRE-I)3-tkLUC were verified by sequencing. The specific mutations of the VDREs in the native CYP24 promoter (?326 to ?22) were introduced by PCR-based site-directed mutagenesis (QuikChange PCR-mediated site-directed mutagenesis kit; Stratagene) using ?326-LUC vector as a template to produce ?VDRE-I ( ?168 CCC mutated to GTT) and ?VDRE-II ( ?289 CACC mutated to AAAA). The ?VDRE-II vector was then used as a template to produce the ?VDRE-I + ?VDRE-II (?VDREs) construct. Primary culture of human hepatocytes. Hepatocytes were prepared from lobectomy segments resected from adult patients for medically required purposes unrelated to our research program. The use of these human hepatic specimens for scientific purposes has been approved by the French National Ethics Committee Hepatocytes were prepared and cultured according to a previously published procedure (56). The cells were plated into collagen-coated dishes at 0.17 × 10 6 cells per square centimeter in a hormonally and chemically defined medium consisting of a mixture of Williams's E medium and Ham's F12 medium (1:1 in volume) Forty-eight hours after plating, cells were cultured in the presence of the indicated concentrations of compounds Two microliters of diluted RT reaction (1:10) was used for real-time PCR amplification seconds seconds seconds), of cDNA encoding amino acids 1?434 of human PXR using oligonucleotides Quantitative PCR. Total RNA was extracted from cells or frozen mouse tissues using TRIZOL reagent (Invitrogen Corp.), according to the manufacturer's instructions. Purity was confirmed by spectrophotometry. cDNAs were synthesized from 1?2 ?g of total RNA using the SuperScript II first-strand synthesis system for PCR (Invitrogen Corp.) at 42°C for 60 minutes, in the presence of random hexamers (Amersham Pharmacia Biotech). Quantification of mRNAs was performed using the LightCycler apparatus The following program was used: a denaturation step at 95°C for 8 minutes, and 50 cycles of PCR all cases, the quality of the PCR product was assessed by monitoring of a fusion step at the end of the run, pp.5-5
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