Alternative pathways for vitamin D metabolism

CYP11A1, best known for its role in initiating steroid hormone synthesis from cholesterol, also acts on vitamins D2 and D3. CYP11A1 hydroxylates the vitamin D3 side chain at C20, C22, C23, and/or C17 producing a number of hydroxyderivatives including 20-hydroxyvitamin D3 (20(OH)D3) and 20,23-dihydroxyvitamin D3 (20,23(OH)2D3). CYP11A1-derived products can be further hydroxylated at C24, C25, and/or C26 by CYP2R1, CYP3A4, CYP24A1, and CYP27A1. Two of the major products, 20(OH)D3 and 1,20(OH)2D3, are present in human serum at higher concentrations than 1,25(OH)2D3. The CYP11A1-derived hydroxyderivatives are biologically active in vitro and in vivo, with effects including inhibiting cell proliferation, promoting differentiation, reducing inflammation and fibrosis, and stimulating the expression of anti-oxidative and DNA-repair enzymes. Unlike 1,25(OH)2D3, they display little or no calcemic activity and thus have greater therapeutic potential. The hydroxyderivatives not only work as biased agonists on the VDR but also exert some of their effects through binding to RORα and γ, LXRα and β, and AhR. Other alternative routes of vitamin D metabolism include 3-epimerization, which produces less active metabolites and conjugation with sulfate and glucuronic acid.