Page 213 - Vitamin D and Cancer

200 F.S.G. Cheung and J.K.V. Reichardt

1a-hydroxylase and VDR knock out mice [120]. These experiments showed that
1,25(OH) D and VDR are both crucial for calcium absorption, longitudinal bone
2
3
growth and normal bone remodeling. Cloning of the CYP27B1 gene [54], showed
that patients with vitamin D-dependant rickets type I had defects in the CYP27B1
gene and are unable to convert 25OHD to 1,25(OH) D On the other hand, patients
3.
2
3
with vitamin D-dependant rickets type II (hereditary vitamin D resistant rickets) do
not have a functioning VDR [49].
The formation of 1,25(OH) D from the hydroxylation of 25OHD by
3
2
3
1a- hydroxylase in the kidneys is regulated by parathyroid hormone (PTH) which in
2+
2+
turn is regulated by Ca levels. The Ca sensing receptor in the parathyroid cell
regulates the secretion of PTH. Secreted PTH then binds to the PTH membrane
receptor of the renal proximal tubular cell to induce cAMP and PIP signaling path-
2
ways (described in Sect. 9.3.3), which leads to the transcriptional activation and
upregulation of CYP27B1 [3]. In addition, the enhanced expression of CYP27B1 can
also be mediated by Ca independent of the PTH pathway but the mechanism
2+
involved in this process is still not well understood [63]. Upregulation of CYP27B1
causes the increased synthesis of the 1a-hydroxylase enzyme which acts on the
intestinal cell through the genomic pathway (described in Sect. 9.3.2) to upregulate
the expression of transient receptor potential vanilliod (TRPV) 5, TRPV 6, calbin-
dins, Ca pump and the Na /Ca exchanger (Table 9.1). These proteins all take part
2+
2+
+
2+
in the transcellular pathway in the uptake of Ca from diet [122]. TRPV5 and
TRPV6 (more abundant in the intestinal cell) are Ca channel proteins on the apical
2+
surface of the intestine that mediate the entry of Ca [156]. Upon entry of the Ca ,
2+
2+
Table 9.1 The effects of 1,25(OH) D in various tissues
2 3
Tissue Protein Gene regulation Effect
Small intestine TRPV 5 Upregulation Entry of Ca into
2+
TRPV 6 Upregulation the intestinal cell
Calbindins Upregulation Ca transport
2+
from entry size
to basolateral
membrane
Ca pump Upregulation Ca exit from
2+
2+
Na /Ca exchanger Upregulation intestinal cell
+
2+
Bone RANKL Upregulation Osteoclastogenesis
OPA Downregualtion Bone cell
differentiation
Skin Involucrin Upregulation Keratinocyte
Transglutaminase K Upregulation differentiation
Loricrin Upregulation
filaggrin Upregulation
CaR Upregulation
PLCg Upregulation
Others (immune – – Regulation of
system, prostate, proliferation and
breast, colon) differentiation