TY - JOUR
T1 - Differences in transactivation between rat CYP3A1 and human CYP3A4 genes by human pregnane X receptor.
AU - Takada, Tomonari
AU - Ogino, Makoto
AU - Miyata, Masaaki
AU - Shimada, Miki
AU - Nagata, Kiyoshi
AU - Yamazoe, Yasushi
N1 - Funding Information:
Acknowledgement: This work was supported by Grant-in-Aid from the Ministry of Education, Sciences and Culture (Ministry of Education, Culture, Sports, Sciences and Technology), and the Ministry of Health and Welfare (Ministry of Health, Labour, and Welfare) of Japan.
PY - 2004/4
Y1 - 2004/4
N2 - In an assay system using a human CYP3A4 reporter constructed with the promoter (+11 nt to -362 nt) and enhancer (-7.2 knt to -7.8 knt) regions including everted repeat separated by six nucleotides (ER-6) and direct repeat separated by three nucleotides (DR-3) motifs, the CYP3A4 transactivation was detected without overexpression of any nuclear receptors in rifampicin-treated HepG2 cells. Overexpression of human pregnane X receptor (hPXR) enhanced the transactivation. Rat CYP3A1 reporter constructed with the promoter region (+31 nt to -171 nt) including both DR-3 and ER-6 motifs was, however, not transactivated in rifampicin-treated cells, even after overexpression of hPXR. Although overexpression of retinoid X receptor alpha (RXRalpha) had no clear effect for both CYP3A reporters, co-expression of apolipoprotein AI regulatory protein-1 (ARP-1) with hPXR resulted in the rifampicin-induced transactivation of the CYP3A1 reporter. A truncated CYP3A4 reporter retaining the both motifs showed the rifampicin-induced transactivation by overexpression of hPXR and ARP-1, while the transactivation in hPXR-overexpressed cells was not observed. These results support the idea that a nuclear receptor other than RXRalpha may play a role in the CYP3A transactivation together with hPXR. The present study also suggests the involvement of a novel cis-element in the hPXR-mediated CYP3A4 transactivation.
AB - In an assay system using a human CYP3A4 reporter constructed with the promoter (+11 nt to -362 nt) and enhancer (-7.2 knt to -7.8 knt) regions including everted repeat separated by six nucleotides (ER-6) and direct repeat separated by three nucleotides (DR-3) motifs, the CYP3A4 transactivation was detected without overexpression of any nuclear receptors in rifampicin-treated HepG2 cells. Overexpression of human pregnane X receptor (hPXR) enhanced the transactivation. Rat CYP3A1 reporter constructed with the promoter region (+31 nt to -171 nt) including both DR-3 and ER-6 motifs was, however, not transactivated in rifampicin-treated cells, even after overexpression of hPXR. Although overexpression of retinoid X receptor alpha (RXRalpha) had no clear effect for both CYP3A reporters, co-expression of apolipoprotein AI regulatory protein-1 (ARP-1) with hPXR resulted in the rifampicin-induced transactivation of the CYP3A1 reporter. A truncated CYP3A4 reporter retaining the both motifs showed the rifampicin-induced transactivation by overexpression of hPXR and ARP-1, while the transactivation in hPXR-overexpressed cells was not observed. These results support the idea that a nuclear receptor other than RXRalpha may play a role in the CYP3A transactivation together with hPXR. The present study also suggests the involvement of a novel cis-element in the hPXR-mediated CYP3A4 transactivation.
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U2 - 10.2133/dmpk.19.103
DO - 10.2133/dmpk.19.103
M3 - Article
C2 - 15499176
AN - SCOPUS:16544364469
VL - 19
SP - 103
EP - 113
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
SN - 1347-4367
IS - 2
ER -