Page 332 - Vitamin D and Cancer

14 Unique Features of the Enzyme Kinetics for the Vitamin D System 319

Legend

Vitamin D from diet or UVB 1 Vitamin D-25-
METABOLITE hydroxylase in Liver
‘COMPARTMENT’
Tissue (non-renal)
2 CYP27B1
Vitamin D 1 Renal 25(OH)D-1-
3 hydroxylase
(CYP27B1)

25(OH)D Renal mitochondrial
4 25(OH)D-24-
2 3 hydroxylase (CYP24)
4 5 Tissue CYP24
1,25(OH) D
2
PANCREAS OR An ‘unregulated’ step
PROSTATE in the flow of
TISSUE PLASMA metabolism
1,25(OH) 2 D 1,25(OH) D
2
5 Each valve
represents a
regulated step in the
24,25(OH) D flow of metabolism
2
and catabolism
6 6 Final Catabolism and
excretion

Fig. 14.1 Conceptual model of vitamin D metabolism and its points of regulation. The vessels
represent virtual body compartments for vitamin D and its major metabolites. The height of mate-
rial in the shaded portion of each vessel represents the relative concentration of metabolite. Open
passages represent stages at which the pertinent enzymes are relatively unregulated. Valves repre-
sent stages at which there is regulation of flow at the enzyme level. A higher supply of 25(OH)D
leads to down-regulation of CYP27B1 and an up-regulation of CYP24. The net effect of this
model is to maintain tissue 1,25(OH) D at the set-point level indicated by the block arrows
2

relevant, the regulation of 1,25(OH) D production is poorly understood. The
2
1,25(OH) D generated in peripheral tissues is not normally released into the circula-
2
tion, and tissue levels of 1,25(OH) D are very difficult to measure. In Fig. 14.1, the
2
valves represent the stages at which hydroxylases of the vitamin D system need to be
regulated. In both the circulation and peripheral tissues, the concentration of
1,25(OH) D needs to be regulated according to serum 25(OH)D concentration. At the
2
endocrine kidney, there are multiple regulatory mechanisms to moderate circulating
1,25(OH) D quickly. In comparison peripheral tissues represent a black box in terms
2
of regulating 1,25(OH) D locally. The control of 1,25(OH) D is a classic engineering
2
2
problem of feedback control. A basic concern for systems is the time it takes for a
system to sense a change in input, to initiate the appropriate response, and for the
response mechanism to fully complete the necessary correction.