Bhagavan Medical Biochemistry 2001, page 940 read online

906

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

(

tretinoin

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

proteins

(CRABPs).

Function

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,

and

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

acutepromyelo-

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

PML

gene located on chromosome

15 with the RARa gene located on chromosome 17. The

two chimeric genes formed are

PML-RARa

and RARa-

PML. Of these, the

PML-RARa

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

PML

and

RARa

genes in differentiation of myeloid pre-

cursors. The normal

PML

gene product has growth sup-

pressor activity. Treatment with all

-trans

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