Cyclic AMP-independent activation of CYP3A4 gene expression by forskolin.
Forskolin and cAMP have been shown to have paradoxical effects in the regulation of expression levels of mRNA of cytochrome P450 3A (CYP3A) family members. We demonstrate in this study that forskolin upregulated the promoter for CYP3A4 independent of its ability to increase cAMP levels. This activity was explained showing forskolin directly activated the pregnane-X-receptor, a known regulator of CYP3A genes.
Dowless
Michele S
MS
Lilly Research Laboratories, Eli Lilly and Co., 20 T.W. Alexander Drive, P.O. Box 13951, Research Triangle Park, NC 27709-3951, USA.
Barbee
James L
JL
Borchert
Kristen M
KM
Bocchinfuso
Wayne P
WP
Houck
Keith A
KA
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D056920:Nuclear Receptor Coactivator 1; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D008024:Ligands; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1