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Biochemical and Molecular Actions of Nutrients

All-trans Retinoic Acid Antagonizes the Action of Calciferol and Its Active Metabolite, 1,25-Dihydroxycholecalciferol, in Rats¹

Department of Safety Sciences, Pfizer Global Research and Development, Ann Arbor, MI 48105 and ^* Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706

²To whom correspondence should be addressed. E-mail: deluca{at}biochem.wisc.edu.

An antagonistic interaction between retinol and calciferol has been established. However, the mechanism by which this antagonism occurs is unclear. One possibility is that retinol affects the metabolism of calciferol. To investigate this hypothesis, retinol- and calciferol-depleted rats were given various amounts of ergocalciferol, cholecalciferol, 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃], or 24,24-difluoro-1,25-dihydroxycholecalciferol [24-F₂-1,25(OH)₂D₃] in combination with various amounts of retinyl acetate or all-trans retinoic acid (ATRA) in a series of studies. Rats administered 1720 or 3440 µg retinyl acetate once every 3 d for 33 d in combination with 25.8 ng ergocalciferol or 25 ng cholecalciferol every 3 d had lower serum calcium and greater serum phosphorus concentrations than rats fed 0 or 11.4 µg retinyl acetate every 3 d. In addition, rats fed 400 µg ATRA/d in combination with 25.8 ng ergocalciferol every 3 d, 25 ng cholecalciferol every 3 d, 2–5 ng 1,25(OH)₂D₃/d, or 0.5–1 ng 24-F₂-1,25(OH)₂D₃/d had significantly lower serum calcium and higher serum phosphorus concentrations than rats not given ATRA in the diet. Therefore, both retinyl acetate and ATRA are able to antagonize the action of ergocalciferol and cholecalciferol in vivo. Additionally, ATRA antagonizes the in vivo action of 1,25(OH)₂D₃ and an analog, 24-F₂-1,25(OH)₂D₃, that cannot be 24-hydroxylated. Together, these results suggest that retinol does not antagonize the action of calciferol by altering the metabolism of calciferol or 1,25(OH)₂D₃, but does so by another mechanism.

KEY WORDS: • calciferol • retinol • retinol-calciferol interaction

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