How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase enzymology

Anticancer Res. 2009 Sep;29(9):3675-84.


The question of what makes an 'optimal' vitamin D intake is usually equivalent to, 'what serum 25-hydroxyvitamin D [25(OH)D] do we need to stay above to minimize risk of disease?'. This is a simplistic question that ignores the evidence that fluctuating concentrations of 25(OH)D may in themselves be a problem, even if concentrations do exceed a minimum desirable level. Vitamin D metabolism poses unique problems for the regulation of 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations in the tissues outside the kidney that possess 25(OH)D-1-hydroxylase [CYP27B1] and the catabolic enzyme, 1,25(OH)2D-24-hydroxylase [CYP24]. These enzymes behave according to first-order reaction kinetics. When 25(OH)D declines, the ratio of 1-hydroxylase/24-hydroxylase must increase to maintain tissue 1,25(OH)2D at its set-point level. The mechanisms that regulate this paracrine metabolism are poorly understood. I propose that delay in cellular adaptation, or lag time, in response to fluctuating 25(OH)D concentrations can explain why higher 25(OH)D in regions at high latitude or with low environmental ultraviolet light can be associated with the greater risks reported for prostate and pancreatic cancers. At temperate latitudes, higher summertime 25(OH)D levels are followed by sharper declines in 25(OH)D, causing inappropriately low 1-hydroxylase and high 24-hydroxylase, resulting in tissue 1,25(OH)2D below its ideal set-point. This hypothesis can answer concerns raised by the World Health Organization's International Agency for Research on Cancer about vitamin D and cancer risk. It also explains why higher 25(OH)D concentrations are not good if they fluctuate, and that desirable 25(OH)D concentrations are ones that are both high and stable.

Publication types

  • Review

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism
  • Humans
  • Neoplasms / enzymology
  • Neoplasms / prevention & control*
  • Steroid Hydroxylases / metabolism
  • Vitamin D / administration & dosage*
  • Vitamin D3 24-Hydroxylase


  • Vitamin D
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase