Page 330 - Vitamin D and Cancer

14 Unique Features of the Enzyme Kinetics for the Vitamin D System 317

Table 14.1 Conceptual issues complicating the vitamin D hypothesis for cancer prevention
• How can latitude and environmental ultraviolet light be associated with increased risk of
prostate cancer [3, 25, 26], and pancreatic cancer [27], yet not be a significant contributor
to the lower average 25(OH)D concentrations theorized to be the key component of the
mechanism that relates latitude to cancer risk [7]?
• Except for gastrointestinal cancer [28], efforts to relate serum 25(OH)D to cancer risk
prospectively have not been prospectively associated with cancer risk
• A U-shaped risk curve has been reported for prostate cancer in relation to serum 25(OH)D
concentrations, suggesting that higher serum 25(OH)D is not necessarily a good thing [29, 30]
• The rate of rise in prostate-specific antigen (PSA) slower in summer than in other seasons
[31] and vitamin D supplementation appears to slow the rate of rise in PSA [32], yet in
epidemiological studies, serum 25(OH)D levels are not related to lower cancer risk
• In regions of the United States where environmental UVB is low, is there a positive
association between pancreatic cancer versus serum 25(OH)D, but in regions where UVB is
high (presumably providing even higher serum 25(OH)D levels), is there no relationship with
25(OH)D [33]

D supplementation or a UV-light environment can do anything to prevent an inter-
nal cancer or to improve prognosis has never been addressed with an in vivo experi-
mental model. Furthermore, an incomplete understanding of the relationships
between vitamin D and cancer has impeded any substantial adjustment in policy to
take advantage the potential role for vitamin D. The World Health Organization,
through its International Agency for Research in Cancer (IARC) published a major
review of cancer and vitamin D [7]. The authors of the IARC report found no com-
pelling reason to change existing public advice about vitamin D. However, the
IARC has joined the National Institutes of Health in calling for randomized clinical
trials to address vitamin D treatment and cancer prevention [7, 23].
There are many arguments against the “vitamin D hypothesis” and cancer.
Serum 25(OH)D levels are similar or even higher in northern Europeans than they
are in the south [7, 24]. An inadequate vitamin D supply per se does not explain for
the positive latitudinal correlation with prostate cancer incidence. Table 14.1 lists
some difficulties that need to be resolved before the vitamin D hypothesis for
cancer prevention can be more widely accepted. The rest of this paper describes
how an understanding of the enzymology of the vitamin D system may help to
resolve the apparently contradictory issues surrounding the roles of vitamin D,
latitude, and ultraviolet light in the context of certain cancers.

14.2 Vitamin D Hydroxylase Enzyme Kinetics

There are several reasons why the paradigm for the vitamin D system is very different
from the rest of endocrinology (Table 14.2). Metabolism in the vitamin D system
behaves according to enzyme-kinetic principles that are very different from those
underlying other hormone control systems. The hydroxylase enzymes that metabolize
25(OH)D in vivo behave according to first-order reaction kinetics. In essence, a dou-
bling in availability of substrate to the enzyme results in a transient doubling in the
rate of product (i.e. 1,25(OH) D) synthesis. After a time, an increase in 25(OH)D
2