chapter 38
Vitamin Metabolism
also functions in transport of thyroid hormones. Inter-
action between transthyretin and RBP is quite specific
(dissociation constant 10“6—10
mol/L). Retinol-RBP-
transthyretin complex (RTC) (M.W. 76,000) migrates
electrophoretically as an a-globulin. Normal concentra-
tions of RBP and transthyretin in human plasma are
40-50 and 200-300 /xg/mL, respectively. Transthyretin,
a glycoprotein with a high tryptophan content, is synthe-
sized in the liver and migrates electrophoretically ahead
of albumin. It has a half-life of 2 days and has a small
pool size. These two properties make it a sensitive in-
dicator of nutritional status (Chapter 17). Its plasma
level decreases in protein-calorie malnutrition, liver dis-
ease, and acute inflammatory diseases. The serum con-
centration of retinol is held remarkably constant despite
wide variation in dietary intake and hepatic stores of the
vitamin by tight control over the concentration of RBP.
In vitamin A-deficient rats, hepatic secretion of RBP
is specifically blocked, and its level in serum falls
whereas that in the liver increases. Administration of
vitamin A causes a rapid proportional release of hepatic
RBP. The rapidity indicates the release of pooled pro-
tein rather than new synthesis. Patients suffering from
parenchymal liver disease or protein-calorie malnutrition
have reduced amounts of serum RBP and vitamin A.
Provision of an adequate diet to malnourished children
increases plasma concentrations of RBP and retinol, even
without vitamin A supplementation, suggesting the pres-
ence of stores of retinol that could not be mobilized on
the inadequate diet. The plasma concentration of RBP in-
creases in renal disease, indicating that the kidney is a
major catabolic site for this protein. Complex formation
with transthyretin reduces glomerular filtration and, con-
sequently, renal catabolism of RBP. In rat hepatocyte cul-
tures, glucocorticoids stimulate net synthesis of RBP.
Oxidation of retinol produces
retinoic acid
The reaction is irreversible. Retinoic acid enters the por-
tal blood, is transported bound to albumin, and is not
stored to any great extent. The concentration of retinoic
acid in plasma is normally 3^4 ng/mL. A biologically
active metabolite, 5,6-epoxyretinoic acid, has been iso-
lated from the intestinal mucosa of vitamin A-deficient
rats following administration of
H-retinoic acid. Sev-
eral tissues have specific
cellular retinoic acid-binding
Vitamin A and its derivatives retinal and retinoic acid
have many essential biological roles in such processes
as vision, regulation of cell proliferation and differen-
tiation, and as morphogenetic agents during embryonic
development and differentiation. Both natural and syn-
thetic analogues (known as retinoids) possess varying de-
grees of biological activity ascribed to vitamin A. Other
than the role of retinal in vision, retinoids exert their bi-
ological actions by binding to specific nuclear receptors,
such as transcription factors that modulate gene expres-
sion. The retinoid receptors belong to two subfamilies:
retinoic acid receptors (RARs) and retinoid X receptors
(RXRs). Both the RARs and RXRs contain three isotypes,
a, p,
encoded by separate genes. Thus, the retinoid
receptor family includes RARa, RAR/3, RARy, RXRa,
RXRyd, and RXRy, which are members of the steroid and
thyroid hormone superfamily of receptors (Chapter 30).
All of these receptors possess at least two domains: a lig-
and binding domain and a DNA binding domain. The DNA
binding domain of the receptor recognizes retinoic acid
response elements within the target gene via the two zinc
finger binding motifs.
The receptors form dimers of various combinations and
permutations within the superfamily, and each dimer may
perform a specific biological function by binding to spe-
cific DNA response elements. Activation of retinoid recep-
tors can lead to inhibition of cell proliferation, induction of
differentiation, and induction of apoptosis during normal
cell development. The importance of RARs in cell prolifer-
ation and differentiation is illustrated by
cytic leukemia
(PML), which is a subtype of acute myeloid
leukemia. PML is characterized by abnormal hypergran-
ular promyelocytes, a cytogenetic translocation, and a
bleeding disorder secondary to consumptive coagulopa-
thy and fibrinolysis. The bleeding problems are presum-
ably initiated by procoagulant phospholipids present in the
leukemic cells (Chapter 36).
The cytogenetic hallmark of PML consists of a balanced
reciprocal translocation between the long arms of chromo-
somes 15 and 17, designated as t( 15; 17) (Figure 38-3). The
translocation results in two recombinant chromosomes,
one abnormally long 15q+ and one shortened 17q- This
translocation fuses the
gene located on chromosome
15 with the RARa gene located on chromosome 17. The
two chimeric genes formed are
and RARa-
PML. Of these, the
gene is transcriptionally
active and produces a PML-RARa protein. This protein,
which is an oncoprotein, is responsible for the pathogen-
esis of PML by interfering with the normal functions of
genes in differentiation of myeloid pre-
cursors. The normal
gene product has growth sup-
pressor activity. Treatment with all
retinoic acid has
produced complete remissions in PML by promoting the
conversion of leukemic blast cells into mature cells. This
is because the PML-RARa oncoprotein maintains respon-
siveness to retinoic acid’s biological actions. Retinoic acid
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