DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

linked to a central cobalt atom and extensively substituted with
methyl, acetamide, and propionamide residues.
2. A 5,6-dimethylbenzimidazolyl nucleotide, which links almost
at right angles to the corrin nucleus with bonds to the cobalt
atom and to the propionate side chain of the C pyrrole ring.
3. A variable R group—the most important of which are found in
the stable compounds cyanocobalamin and hydroxocobalamin
and the active coenzymes methylcobalamin and 5-deoxyadenosylcobalamin.
The terms vitamin B 12
and cyanocobalamin are used interchangeably
as generic terms for all of the cobamides active in humans.
Preparations of vitamin B 12
for therapeutic use contain either
cyanocobalamin or hydroxocobalamin because only these derivatives
remain active after storage.
Metabolic Functions. The active coenzymes methylcobalamin
and 5-deoxyadenosylcobalamin are essential
for cell growth and replication. Methylcobalamin
is required for the conversion of homocysteine to
methionine and its derivative S-adenosylmethionine.
In addition, when concentrations of vitamin B 12
are
inadequate, folate becomes “trapped” as methyltetrahydrofolate
to cause a functional deficiency of other required
intracellular forms of folic acid (see Figures 37–6 and
37–7 and preceding discussion). The hematologic
abnormalities in vitamin B 12
–deficient patients result
from this process. 5-Deoxyadenosylcobalamin is
required for the re-arrangement of methylmalonyl CoA
to succinyl CoA (Figure 37–6).
Sources in Nature. Humans depend on exogenous
sources of vitamin B 12
. In nature, the primary sources
are certain microorganisms that grow in soil, sewage,
water, or the intestinal lumen of animals that synthesize
the vitamin. Vegetable products are free of vitamin
B 12
unless they are contaminated with such microorganisms,
so that animals are dependent on synthesis in
their own alimentary tract or the ingestion of animal
products containing vitamin B 12
. The daily nutritional
requirement of 3-5 μg must be obtained from animal
by-products in the diet. Despite this, strict vegetarians
rarely develop vitamin B 12
deficiency. Some vitamin
B 12
is available from legumes, which are contaminated
with bacteria capable of synthesizing vitamin B 12
, and
vegetarians often fortify their diets with a wide range of
vitamins and minerals.
Absorption, Distribution, Elimination, and Daily
Requirements. In the presence of gastric acid and pancreatic
proteases, dietary vitamin B 12
is released from
food and salivary binding protein and bound to gastric
intrinsic factor. When the vitamin B 12
–intrinsic factor
complex reaches the ileum, it interacts with a receptor
on the mucosal cell surface and is actively transported
into circulation. Adequate intrinsic factor, bile, and
sodium bicarbonate (to provide a suitable pH) all are
required for ileal transport of vitamin B 12
. Vitamin B 12
deficiency in adults is rarely the result of a deficient diet
per se; rather, it usually reflects a defect in one or
another aspect of this complex sequence of absorption
(Figure 37–8). Achlorhydria and decreased secretion of
intrinsic factor by parietal cells secondary to gastric
atrophy or gastric surgery is a common cause of vitamin
B 12
deficiency in adults. Antibodies to parietal cells or
intrinsic factor complex also can play a prominent role
in producing a deficiency. A number of intestinal diseases
can interfere with absorption, including pancreatic
disorders (loss of pancreatic protease secretion),
bacterial overgrowth, intestinal parasites, sprue, and
localized damage to ileal mucosal cells by disease or
as a result of surgery.
Once absorbed, vitamin B 12
binds to transcobalamin
II, a plasma β-globulin, for transport to tissues.
Two other transcobalamins (I and III) also are present
in plasma; their concentrations are related to the rate
of turnover of granulocytes. They may represent
2
1
DIET
Intrinsic
Factor-B 12
Complex
3-8 μg
4
TcII-B 12
"Releasing
Factor"
3
Hepatic B 12 Stores
1-10 mg
+ CH 3
Methyl
B 12
Liver
TcI-B 12
and
6 TcIII-B 12
Tissue
Deoxyadenosyl
B 12
B 12
Figure 37–8. The absorption and distribution of vitamin B 12
.
Deficiency of vitamin B 12
can result from a congenital or acquired
defect in any one of the following: (1) inadequate dietary supply;
(2) inadequate secretion of intrinsic factor (classical pernicious
anemia); (3) ileal disease; (4) congenital absence of transcobalamin
II (TcII); or (5) rapid depletion of hepatic stores by interference
with reabsorption of vitamin B 12
excreted in bile. The utility
of measurements of the concentration of vitamin B 12
in plasma to
estimate supply available to tissues can be compromised by liver
disease and (6) the appearance of abnormal amounts of transcobalamins
I and III (TcI and III) in plasma. Finally, the formation of
methylcobalamin requires (7) normal transport into cells and an
adequate supply of folic acid as CH 3
H 4
PteGlu 1
.
7
5
1089
CHAPTER 37
HEMATOPOIETIC AGENTS