The Role of Intestinal Cytochrome P450s in Vitamin D Metabolism

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2024-06, Vol.14 (6), p.717
• Main Authors: Uga, Minori, Kaneko, Ichiro, Shiozaki, Yuji, Koike, Megumi, Tsugawa, Naoko, Jurutka, Peter W, Miyamoto, Ken-Ichi, Segawa, Hiroko
• Format: Article
• Language: English
• Subjects: 1,25(OH)2D3; 25OHD3; Alfacalcidol; Amino acids; Animals; Bone density; Bones; Calcifediol; Calcitriol; Calcitriol - metabolism; CYP24A1; CYP3A; Cytochrome; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Density; Enzymes; Epithelial cells; Ethylenediaminetetraacetic acid; Gastrointestinal diseases; Gene expression; Humans; Hydroxylation; Intestinal Mucosa - metabolism; Intestines - enzymology; Kidneys; Liver; Metabolism; Mice; Mitochondria; Parathyroid hormone; Peptides; Physiological aspects; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Rickets; Small intestine; Vitamin D; Vitamin D - metabolism; Vitamin D receptors; Vitamin D-dependent rickets; Vitamin D3; Vitamin D3 24-Hydroxylase - genetics; Vitamin D3 24-Hydroxylase - metabolism; Vitamin deficiency
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom14060717

Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D [1,25(OH) D ]. 1,25(OH) D controls gene expression through the nuclear vitamin D receptor (VDR) mainly expressed in intestinal epithelial cells. Cytochrome P450 (CYP) 24A1 is a catabolic enzyme expressed in the kidneys. Interestingly, a recently identified mutation in another CYP enzyme, CYP3A4 (gain-of-function), caused type III vitamin D-dependent rickets. CYP3A are also expressed in the intestine, but their hydroxylation activities towards vitamin D substrates are unknown. We evaluated CYP3A or CYP24A1 activities on vitamin D action in cultured cells. In addition, we examined the expression level and regulation of CYP enzymes in intestines from mice. The expression of CYP3A or CYP24A1 significantly reduced 1,25(OH) D -VDRE activity. Moreover, in mice, mRNA was significantly induced by 1,25(OH) D in the intestine, but a mature form (approximately 55 kDa protein) was also expressed in mitochondria and induced by 1,25(OH) D , and this mitochondrial enzyme appears to hydroxylate 25OHD to 24,25(OH) D . Thus, CYP3A or CYP24A1 could locally attenuate 25OHD or 1,25(OH) D action, and we suggest the small intestine is both a vitamin D target tissue, as well as a newly recognized vitamin D-metabolizing tissue.