19nor-1,25-dihydroxyvitamin D2 specifically induces CYP3A9 in rat intestine more strongly than 1,25-dihydroxyvitamin D3 in vivo and in vitro.
In the intestine, the vitamin D receptor is activated by 1alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3] to perform its function in calcium homeostasis, or it is activated by lithocholic acid when its levels are elevated after a meal. Both ligands transcriptionally up-regulate the mRNA of enzymes belonging to the CYP3A subfamily, increasing the metabolism of a variety of carcinogens, drugs, and hormones. Of the cytochrome P450 enzymes, the CYP3A subfamily is the most abundant in liver and intestine and has the widest range of substrate specificity. In addition to being a ligand for the vitamin D receptor, lithocholic acid is also a substrate for CYP3A enzymes. Lithocholic acid causes colon cancer; thus, decreasing lithocholic acid levels in the intestine by up-regulating CYP3A enzymes with 1,25(OH)2 D3 analogs may have therapeutic value in the prevention of colon cancer. We investigated the induction of CYP3A9 by 1,25(OH)2D3 and 19nor-1alpha,25-dihydroxyvitamin D2[19nor-1,25(OH)2 D2]. We observed the that latter analog, currently used to treat renal osteodystrophy, is more efficacious than 1,25(OH)2 D3 in inducing CYP3A9 in rat intestines. CYP3A9 mRNA was maximally elevated 5 to 7 h after a single dose of 1,25(OH)2 D3 to rats and then gradually returned to baseline. We performed promoter deletion analysis of the rat CYP3A9 promoter and identified one proximal vitamin D response element located at -119 to -133 from the transcriptional start site, which is responsible for a large part of the 1,25(OH)2D3 response, and two other vitamin D response elements located at -726 to -744 and at -754 to -776, which together are responsible for the increased sensitivity of CYP3A9 to 19nor-1,25(OH)2D2.
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Dr., Madison, WI 53706, USA.
Claudia
C
Zierold
Jamie A
JA
Mings
Hector F
HF
Deluca
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002112:Calcifediol / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology*; D003001:Cloning, Molecular; D017931:DNA Primers; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007700:Kinetics; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects
D017931:DNA Primers; D012333:RNA, Messenger; D001189:Aryl Hydrocarbon Hydroxylases; C415842:Cyp3a9 protein, rat; D010089:Oxidoreductases, N-Demethylating; D002117:Calcitriol; D002112:Calcifediol