section 38.1

Fat-Soluble Vitamins

907

FIG U RE 38-3

Karyotype of a promyelocytic leukemic cell, with balanced reciprocal translocation between chromosomes 15 and 17,

t(15; 17). The rearranged chromosomes are identified by arrows. (Courtesy of Dr. Mark H. Bogart.)

therapy may also augment the degradation of the PML-

RARa fusion protein. Transgenic mice with a PML-RARa

fusion gene develop PML, which supports the pathogenic

role of the fusion protein in human PML.

Retinyl phosphate, acting as a sugar carrier in a manner

similar to that of dolichol phosphate (Chapter 16), may

be necessary for normal glycosylation of a subgroup of

essential glycoproteins. In vitamin A deficiency, synthe-

sis of some glycoproteins is decreased. Retinyl phosphate

and mannosyl phosphoryl retinol have been identified

in vivo

and have been synthesized

in vitro

using biological

preparations. In rat liver, GDP-mannose: retinyl phosphate

mannosyltransferase has its highest specific activity in the

endoplasmic reticulum. However, retinoic acid can fully

support growth in the whole animal even though it is not

converted to retinol and does not participate in sugar trans-

fer reactions.

More than 1500 retinoids have been synthesized. Two

in particular, 13-cA-retinoic acid (isotretinoin) and etreti-

nate (Figure 38-4), have generated considerable interest

as agents for the treatment of dermatological disorders.

13-cA retinoic acid inhibits sebum production, is the drug

of choice for treatment of severe cystic acne, and is useful

in the treatment of other forms of acne. Etretinate is used

in Europe for treatment of psoriasis and related disorders.

Hypo- and Hypervitaminosis A

Serious vitamin A deficiency is not a major public health

problem in North America; however, where poverty and

poor nutrition are common many persons suffer from

vitamin A deficiency with active corneal involvement.

This condition leads to permanent blindness in about half

of cases, and many of those affected are preschool chil-

dren. Night blindness occurs early in vitamin A deficiency.

There is a reduction in rhodopsin concentration, followed

by retinal degeneration and loss of photoreceptor cells.

Degenerative changes may be due to instability of free

opsin or may indicate an additional nutritive function for

retinaldehyde (or retinoic acid) in retinal cells. The degen-

erative changes of retinitis pigmentosa, a relatively com-

mon, inherited cause of blindness, closely resemble those

of vitamin A deficiency.

Ingestion of vitamin A in large excess of the RDA can

cause toxicity. Daily intake of more than 7500 retinol

equivalents (25,000 IU) is not recommended, and doses

in excess of 3000 retinol equivalents (10,000 IU) should

only be used with medical supervision. Acute toxicity after

FIG U R E 38-4

Structures of 13-ciV-retinoic acid (isotretinoin) (a) and etretinate (b),

synthetic retinoids used as pharmacological agents.