Page 333 - Vitamin D and Cancer

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14.2.2 Vitamin D Cellular Adaptation

In the fields of biochemistry and cellular biology, the time required for an enzyme
to respond to a change in environment (e.g. a change in vitamin D supply) has been
assumed to be so fast that the duration of disequilibrium insignificant. Few publica-
tions have addressed the rate of adaptation of the vitamin D hydroxylases to
changes in vitamin D supply [34–37]. What we know is that endocrine adjustments
to 1,25(OH) D in response to calcium or to changes in 25(OH)D take about 3 days
2
[34, 35, 37]. However, the endocrine secretion of 1,25(OH) D (i.e. what we mea-
2
sure in serum or plasma) is regulated at the kidney by at least three mechanisms:
by plasma calcium, parathyroid hormone [PTH], and through direct feedback by
the product, 1,25(OH) D. In contrast, regulation of paracrine, non-renal 1,25(OH) D
2
2
production is poorly understood. Outside the kidney, there is no regulation of
1,25(OH) D production by calcium or PTH [38]. Because they lack the multiple
2
systems to regulate CYP27B1 and CYP24, the prostate and pancreas probably do
take longer than the kidney to adapt to altered vitamin D supply.

14.2.3 Vitamin D Modulation of Hydroxylases

If the concentration of 1,25(OH) D within cells beyond the kidneys is mediated
2
by the ratio between 25(OH)D-1-hydroxylase and 1,25(OH) D-24-hydroxylase
2
(CYP27B1/CYP24 ratio), then the negative impact of higher CYP24 could be
described as the product of an “oncogene” [39–41]. A relative excess of CYP24
lowers the tissue concentration of 1,25(OH) D that promotes cellular differentia-
2
tion and reduces replication [42, 43]. Conversely, CYP27B1 could be described
as “a tumor suppressor” [44]. Prostate cancer cells, both primary cultured cells
and cell lines, possess lower CYP27B1 activity than normal cells from the pros-
tate, making them partly resistant to the tumor suppressor activity of circulating
25(OH)D [45–47]. If CYP27B1 and CYP24 need to be maintained in a ratio that
compensates for changes in circulating 25(OH)D levels, then the reportedly
lower cellular CYP27B1 within prostate cancer cell lines suggests that those
cells have lost some of their ability to adapt to low 25(OH)D concentrations
(Fig. 14.2).

14.3 Vitamin D and Cancer Risk: Sun Exposure
and Levels of 25(OH)D

If prostate and pancreas are particularly slow to adapt to declining 25(OH)D con-
centrations, then rates of these types of cancer could increase with latitude despite
average 25(OH)D concentrations that may not necessarily trend downwards with