Page 15 - Vitamin D and Cancer

2 H.S. Cross

Keywords Expression of extrarenal vitamin D hydroxylases • Cancer prevention •
Regulation of colonic vitamin D synthesis • Calcium • Estrogens

1.1 Introduction

The enzyme 25-hydroxyvitamin D3-1a-hydroxylase (CYP27B1) plays a central
role in calcium homeostasis [1], but alternative physiological actions have been
suspected for decades. The enzyme catalyzes the conversion of 25-hydroxyvitamin
D (25-(OH)D ) to the hormone 1,25-dihydroxyvitamin D (1a,25-(OH) D ) that is
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known to regulate calcium and phosphate transport in intestine, bone, and kidney.
While initially it was thought that only proximal tubule kidney cells express
CYP27B1, it became evident in the mid-1980s that extrarenal cells, for instance,
bone cells, macrophages, and keratinocytes (see, e.g., [2]) could also express
CYP27B1 enzymatic activity in vitro. Mawer et al. [3] demonstrated that certain
lung cells had measurable CYP27B1 activity. Apparently, this particular
25-hydroxyvitamin D3-1a-hydroxylase was not up-regulated by PTH and was not
down-regulated by plasma calcium, a hallmark of the renal enzyme. In addition,
while in renal cells sufficiency of serum 1,25-(OH) D concentration leads to induc-
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tion of the vitamin D-inactivating enzyme 1,25-(OH) D –24-hydroxylase
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(CYP24A1) [4], the extrarenal CYP27B1 is not necessarily inversely correlated
with CYP24A1 expression, a fact that will be enlarged upon later in this chapter.
While extrarenal CYP27B1 activity in macrophages might be the reason for the
hypercalcemia associated with sarcoidosis and lymphomas, there was also the pos-
sibility that it might be coded by a gene different from the renal one, and this could
lead to alternative regulatory mechanisms. The renal CYP27B1 is a combination of
three proteins: a cytochrome P450 as well as two other proteins, ferredoxin and
ferredoxin reductase. Purified preparations of these proteins possess the CYP27B1
enzyme activity in vitro [5]. These enzyme complexes were cloned from rodents
and human renal cells and response elements were found in promoter regions that
allow up-regulation by PTH. Proof was provided that extrarenal CYP27B1 is a
product of the same gene as the renal form. However, regulation of the newly dis-
covered CYP27B1 suggested existence of a paracrine loop in extrarenal tissues for
the modification of cellular proliferation and differentiation, though subsequent
conversion of the active vitamin D metabolite into a C-24 oxidation product by
CYP24A1 was similar to renal catabolism [6].
In the last few decades, there has been growing appreciation for the multitude of
physiological roles that vitamin D has in many body tissues. As early as in 1979,
Stumpf et al. demonstrated that cells from heart, stomach, pancreas, colon, brain,
skin, gonads, etc., have the nuclear receptor for 1,25-(OH) D [7], the so-called
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vitamin D receptor (VDR), and such tissues are potential targets for 1,25-(OH) D
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activity. Many of these VDR-positive tissues are also positive for CYP27B1, i.e.,
the enzyme that can convert 25-(OH)D to the active metabolite [8], and many of
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these tissues are known to be targets for development of malignancies.