Page 16 - Vitamin D and Cancer

1 Vitamin D: Synthesis and Catabolism 3

As mentioned above, regulation of CYP27B1 in these non-renal tissues differs
from that observed in the kidney and, importantly and in contrast to the renal
enzyme, may be dependent on substrate concentration for activity. This led to the
novel concept that maintenance of adequate serum 25-(OH)D levels would be
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essential for providing the substrate for the synthesis of the active metabolite at
extrarenal sites, which in turn would have physiological functions apart from those
involved in bone mineral metabolism. This concept will be enlarged upon in the
following. Evidence will be provided for the function and regulation of vitamin D
synthesizing and catabolic hydroxylases, i.e., CYP27B1 and CYP24A1, respec-
tively, in colorectal, prostate, and mammary gland-derived cells that are from
organs particularly affected by sporadic malignancies during advancing age.

1.1.1 1,25-(OH) D Synthesis
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7-Dehydrocholesterol, the immediate precursor in the cholesterol biosynthetic
pathway, is produced in rather large quantities in the skin of most vertebrates, also
humans. Ageing decreases the capacity of skin to produce 7-dehydrocholesterol by
as much as 75% [9] and this is of particular relevance when considering that spo-
radic cancers occur primarily in the elderly. When exposed to sunlight, skin cells
absorb UVB radiation with wavelengths of 290–315 nm leading to a rearrangement
of the molecular structure of 7-dehydrocholesterol to form the more thermody-
namically stable previtamin D . Protection of the skin by topical sunscreens will
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reduce previtamin D production by almost 100%. Persons that have greater
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amounts of melanin in their epidermis require much higher exposure to sunlight
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than whites to avoid vitamin D deficiency. Living at geographic latitudes above 35
will not provide enough UVB photons for sufficient production of vitamin D in
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skin during winter time (for further reading see, e.g., [10]). Very few foods natu-
rally contain vitamin D. Cod liver oil and oily fish are the best dietary source which,
in some Scandinavian countries, can provide a positive balance to the lack of der-
mal vitamin D production.
Vitamin D is first hydroxylated in the liver by CYP27A1, a cytochrome P450
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25-hydroxylase, to the precursor 25-(OH)D . To be fully active, 25-(OH)D must
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be converted to 1,25-(OH) D by CYP27B1, a mitochondrial cytochrome P450
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enzyme present primarily in proximal renal tubule cells but also in many extrarenal
cells [11]. While the hormone regulates calcium and phosphate metabolism in
intestine, bone, and kidney, at extrarenal sites it has a wide range of biological
effects that are essentially noncalcemic in nature. The most surprising one is its
ability to suppress hyperproliferative growth of cells and to support differentiation.
In 1982, Tanaka et al. [12] provided the first evidence that 1,25-(OH) D was able
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to promote differentiation of HL-60 leukemia cells. This, and a pronounced antimi-
totic effect, has subsequently been shown for many types of cancer cells in vitro
(see, e.g., [13–18]), though only at nanomolar concentrations. However, serum
1,25-(OH) D never exceeds picomolar concentrations, regardless of whether
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