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.