The genomic actions of 1,25-dihydroxyvitamin D (1,25(OH)D) are mediated by the intracellular vitamin D receptor (VDR). Although immunocytochemistry has shown that disruption of microtubular assembly prevents nuclear access of the sterol-VDR complex, the role of microtubules in the response to 1,25(OH)D has not been studied in viable cells. Our studies examined this interaction in normal human monocytes. Monocytes convert 25(OH)D to 1,25(OH)D and to 24-hydroxylated metabolites more polar than 1,25(OH)D. Microtubule disruption totally abolished the ability of exogenous 1,25(OH)D to suppress its own synthesis and to induce 24-hydroxylase mRNA and activity, without affecting either total 1,25(OH)D uptake or maximal 1,25(OH)D-VDR binding. Thus, intact microtubules are essential for 1,25(OH)D-dependent modulation of gene transcription. Interestingly, microtubule disruption also decreased monocyte 1,25(OH)D synthesis, not by decreasing the V of monocyte mitochondrial 1-hydroxylase but through an increase in the K for 25(OH)D. We examined 25(OH)D transport. Microtubule disruption did not affect total cellular 25(OH)D uptake but reduced its intracellular trafficking to the mitochondria. Thus, microtubules participate in intracellular 25(OH)D transport, and their integrity determines normal 1,25(OH)D synthesis.

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