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

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

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

Vieth R.
Department
of Nutritional Sciences, University of Toronto, and Pathology and
Laboratory Medicine, Mount Sinai Hospital, Toronto, M5G 1X5, ON,
Canada.

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.