Page 310 - Vitamin D and Cancer

13 Vitamin D and Colorectal Cancer 297

differences in vitamin D gastrointestinal absorption and/or metabolism. With the
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exception of fish, eggs and vitamin D fortified foods, the human diet is not an vital
source of vitamin D [6, 7]. Because more than 90% of vitamin D is produced by
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exposure of the skin to sunlight, inadequate exposure to sunlight is the leading
cause of vitamin D deficiency in humans [6–9]. In humans, ultraviolet light cata-
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lyzes the conversion of 7-dehydroxycholesterol to cholecalciferol (vitamin D ).
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Vitamin D is then sequentially metabolized in the liver by a number cytochrome
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P450 enzymes (cyp27A1, cyp 2J3, cyp 2R1 and cyp3A4) to 25-hydroxyvitamin D
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(25-D ) and by 1a-hydroxylase (cyp 27B1) in the kidney to form calcitriol, the
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biologically most active form of vitamin D . Renal 24-hydroxylase (24-OHase, cyp
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24A 1), is the major vitamin D inactivating enzyme [10–13]. Simplified vitamin
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D activation and inactivation oxidative metabolism pathways are shown in
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Fig. 13.1 These vitamin D activating and inactivating cytochrome P450 enzymes
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show wider tissue distribution than previously reported. In addition to the classical
tissues (gastrointestinal mucosa, liver and kidney), substantial variations in vitamin
D activating and inactivating cytochrome P450 enzymes have been reported in a
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variety of human lung, colon, breast and prostate cancer cell lines and in tissue
samples derived from healthy volunteers and cancer patients [14–17]. Recent
reports have also identified other non classical vitamin D metabolizing cytochrome
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P450 enzymes that contribute to the 1a-hydroxylation and 24-hydroxylation of
vitamin D hydroxylation [18–20].
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The contribution of imbalances in cytochrome P450 enzyme activities that acti-
vate and inactivate vitamin D in the pathogenesis of vitamin D deficiency and the
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responses to vitamin D -based therapies in cancer patients has not been fully
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investigated.
13.1.2.2 Assessment of Vitamin D Status
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The serum 25-Hydroxy D (25-D ) level is the generally accepted and the best
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indicator of vitamin D status in humans [21, 22]. The utility of 25-D level in
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assessing vitamin D status is based on its long serum half life (ranging from 2 to
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6 weeks), because its synthesis is unregulated, and that serum 25-D levels reflect
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the overall supply of vitamin D metabolic precursors [23]. There is no universally
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accepted optimal serum 25-D level. The most widely accepted classification
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of vitamin D status based on serum 25-D measurement in humans consists of
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six categories [24]: (i) vitamin D deficiency (serum 25-D levels <20 ng/mL),
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(ii) vitamin D insufficiency (serum 25-D 20–32 ng/mL), (iii) vitamin D suffi-
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ciency ³ 32–100 ng/mL, (iv) vitamin D excess >100 ng/mL, and (v) vitamin D
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intoxication (serum 25-D >150 ng/mL). High performance liquid chromatography
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(HPLC) with UV detection method is accepted as the gold standard for measuring
serum 25-D levels [25–27]. The HPLC assay is, however, time consuming, often
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requires large sample volumes and is not free of inaccuracies in serum 25-D quan-
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titation. The three FDA approved and most commonly used analytical assays for
measuring serum 25-D levels are: Nichols Diagnostics fully automated
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