Vitamin A metabolism

Clinical pharmacology: vitamin A metabolism (absorption, transport, metabolism, excretion)

1. Domina Petric, MD
Vitamin A: metabolism

2. Absorption of vitamin A
I.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

3. Absorption of retinoids
•Most of the preformed vitamin A in the
diet is in theform of retinylesters.
•Retinylesters are hydrolyzedin the
lumen of the small intestine to yield
retinol.
•This step is catalyzed by hydrolases
produced bythepancreas and situated
on the mucosal brushborderor intrinsic
to the brush border itself.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

4. Absorption of retinoids
•The retinylesters, as well as the carotenoids,
are hydrophobicand,thus,depend on
micellar solubilizationfor theirdispersion in
the aqueous environment of the small
intestinal lumen.
•VitaminA is poorlyutilized from low-fat diets!
•The micellar solubilizationof vitamin A
facilitates access of soluble hydrolytic
enzymes to theirsubstrates.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

5. Absorption of retinoids
The overall absorption of retinol from retinyl
esters appears to be fairlyhigh (about 75%).
This process appears to beminimally affected by
the level and type of dietaryfat, although the
absorption is appreciably less efficient at very
high vitamin A doses .
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

6. Absorption of retinoids
VitaminA can also beabsorbed via non
lymphatic pathways.
In mammals, the portal system may be an
important alternative route of vitamin A
absorptionwhen the normal lymphatic pathway
is blocked.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

7. Absorption of carotenoids
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

8. Carotenoid metabolismlinked
to absorption
•Some carotenoids can be provitaminsA because they
can be metabolized to yield retinal due to the action
of retinal-forming carotene dioxygenases.
•Most of this bioconversion occurs via the central
cleavage of the polyene moiety by a predominantly
cytosolic enzyme, β-carotene 15,15′-dioxygenase,found
in the intestinal mucosa, liver and corpusluteum.
•The enzyme requires iron as a cofactor.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

9. Retinoid metabolismlinked to
absorption
•Retinal produced by at least the central cleavage step
is reduced in the intestinal mucosa to retinol.
•This step is catalyzed by another enzyme, retinaldehyde
reductase, which is also found in the liver and eye.
•The reduction requires a reduced pyridine nucleotide
(NADH/NADPH) as a cofactor.
•This step can be catalyzed by a short-chain alcohol
dehydrogenase/aldehyde reductase.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

10. Mucosal metabolism of retinol
•Retinol, formed either from the hydrolysis of
dietaryretinylesters or from the reduction of
retinal cleavedfrom β-carotene, is absorbed
by facilitated diffusionvia a specific
transporter.
•Then, retinol is quicklyre-esterified with long-
chain fatty acids in the intestinal mucosa.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

11. Mucosal metabolism of retinol
•Vitamin A is transported to the liver mainly (80 to 90% of
a retinol dose) in the form of retinylesters.
•The composition of lymph retinylesters isindependent
of the fatty acid compositionof the most recent meal.
•Retinylpalmitate typicallycomprises about half of the
total esters.
•Retinylstearate comprises about a quarter.
•Retinyloleateand retinyllinoleate are present in small
amounts.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

12. Two pathways for the enzymatic reesterificationof
retinol are:
A low-affinity routeinvolves uncomplexed retinol.
•It is catalyzed by acyl-CoA: retinol
acyltransferase.
A high-affinity route involves retinol complexed
with a specific binding protein, cellular retinol-
binding protein type II.
•It is catalyzed by lecithin–retinol acyltransferase.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

13. Vitamin A transport
II.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

14. Retinylesters
Retinylesters are secreted from the
intestinalmucosal cells in the hydrophobic
cores of chylomicron particles, by which
absorbed vitamin A istransported to the
liver through the lymphatic circulation,
ultimately entering the plasma
compartmentthrough the thoracic duct.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

15. Transport of carotenoids
Carotenoids that are not
metabolized atthe intestinalmucosa
are transported from that organ by
chylomicravia the lymphatic
circulation to the liver, wherethey
are transferred to lipoproteins.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

16. Transport of carotenoids
The hydrocarbon carotenoids are
transported primarily in low-density
lipoproteins (LDLs).
The more polar carotenoids aretransported
in a more evenly distributedmanner among
LDLs and high-density lipoproteins(HDLs).
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

17. Transport of carotenoids
β-carotene isretained by the
chylomicron remnants to be
internalized by the liver for
subsequentsecretion in very low
density lipoproteins (VLDLs).
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

18. Impact of abetalipoproteinemia
•The absorption of vitamin A (as well as the other fatsoluble
vitamins) is a particular problem in patients
with abetalipoproteinemia.
•These patients lack apo B and can not synthesize any of the
apo B-containing lipoproteins: LDLs, VLDLs, chylomicra.
•Having no chylomicra, they show hypolipidemia and low
plasma vitamin A levels.
•When given oral vitamin A supplementation, their plasma
levels are normal.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

19. Storage of vitamin A in the liver
•Newly absorbed retinylesters are taken up by the
liver in association with chylomicron remnants by
receptor-mediatedendocytosis on the part of liver
parenchymal cells.
•Within those cells, remnants aredegraded by
lysosomal enzymes.
•Retinol can be transferred from the parenchymal
cells to stellate cells,where it is re-esterified.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

20. Retinyl ester hydrolysis
•Vitamin A is mobilized as retinol from the liver by
hydrolysis of hepatic retinylesters.
•This mobilizationaccounts for about 55% of the
retinol discharged tothe plasma (the balance
comes from recycling fromextrahepatic tissues).
•The retinylester hydrolaseinvolved in this
processshows extreme variationbetween
individuals.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

21. Retinol-binding protein
Once mobilized from liver
stores, retinol is transported to
peripheral tissues by means of a
specificcarrier protein, plasma
retinol-binding protein (RBP).
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

22. Transport of retinoids
The transport, storage, and
metabolism of the retinoidsinvolve
their binding to several other binding
proteins, such as cellular retinol-
binding protein types I and II, and
cellular retinoic acid-binding protein
types I and II.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

23. Cellular uptake of retinol
•Due to their hydrophobic character, the
plasmamembranes do not present a barrier
to retinoluptake.
•Retinolcan enter target cells bynonspecific
partitioning into the plasma membranefrom
RBP,butmost of the vitamin appearsto enter
cells through specific RBP(receptor-mediated
mechanisms).
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

24. Retinol recycling
The majority of retinol
that leaves the plasma
appears to be recycled.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

25. Plasma retinol homeostasis
In healthy individuals,
plasma retinol is maintained
within a narrow range:
40–50 mg/ml in adults.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

26. Vitamin A in adipose tissue
Appreciable amounts
of vitamin A are stored
in adipocytes: 15–20%
of total body store.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

27. Milk retinol
Retinol is transferred
from mother to
infant throughmilk.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

28. Metabolism of vitamin A
III.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

29. Metabolism of vitamin A
The metabolism of vitamin Acenters
around the transport form, retinol, and the
variousroutes of conversion available to it:
•esterification
•conjugation
•oxidation
•isomerization
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

30. Excretion of vitamin A
IV.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

31. Excretion of vitamin A
•Vitamin A is excreted in various forms in
both theurine and feces.
•Under normal physiological conditions,
the efficiency of enteric absorption of
vitaminA is high (80–95%), with 30–60%
of the absorbedamount being deposited
in esterified form in the liver.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

32. •Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
Literature
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.