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

common practice to describe megaloblastic anemia as Addisonian
pernicious anemia. Although Combe suggested that the disorder
might have some relationship to digestion, it was Austin Flint who
in 1860 first described the severe gastric atrophy and called attention
to its possible relationship to the anemia.
After the observation by Whipple in 1925 that liver is a source
of a potent hematopoietic substance for iron-deficient dogs, Minot and
Murphy carried out Nobel Prize–winning experiments that demonstrated
the effectiveness of the feeding of liver to reverse pernicious anemia.
Soon thereafter, Castle defined the need for both intrinsic factor, a
substance secreted by the parietal cells of the gastric mucosa, and extrinsic
factor, the vitamin-like material provided by crude liver extracts.
Nearly 20 years passed before Rickes and coworkers and Smith and
Parker isolated and crystallized vitamin B 12
; Dorothy Hodgkin received
the Nobel Prize for determining its x-ray crystal structure.
As attempts were being made to purify extrinsic factor, Wills
and her associates described a macrocytic anemia in women in India
that responded to a factor present in crude liver extracts but not in the
purified fractions known to be effective in pernicious anemia. This
factor, first called Wills’ factor and later vitamin M, is now known to
be folic acid. The term folic acid was coined by Mitchell and
coworkers in 1941, after its isolation from leafy vegetables.
More recent work has shown that neither vitamin B 12
nor
folic acid as purified from foodstuffs is the active coenzyme in
humans. During extraction, active labile forms are converted to stable
congeners of vitamin B 12
and folic acid, cyanocobalamin and
pteroylglutamic acid, respectively. These congeners must then be
modified in vivo to be effective. Although a great deal has been
learned about the intracellular metabolic pathways in which these
vitamins function as required cofactors, many questions remain,
among them: what is the relationship of vitamin B 12
deficiency to
the neurological abnormalities that occur with this disorder?
Relationships Between Vitamin B 12
and Folic Acid. The
major roles of vitamin B 12
and folic acid in intracellular
metabolism are summarized in Figure 37–6.
Intracellular vitamin B 12
is maintained as two active
coenzymes: methylcobalamin and deoxyadenosylcobalamin.
Deoxyadenosylcobalamin (deoxyadenosyl B 12
)
is a cofactor for the mitochondrial mutase enzyme that
catalyzes the isomerization of l-methylmalonyl CoA to
succinyl CoA, an important reaction in carbohydrate and
lipid metabolism. This reaction has no direct relationship
to the metabolic pathways that involve folate. In
contrast, methylcobalamin (CH 3
B 12
) supports the
methionine synthetase reaction, which is essential for
normal metabolism of folate (Weissbach, 2008).
Methyl groups contributed by methyltetrahydrofolate
(CH 3
H 4
PteGlu 1
) are used to form methylcobalamin,
which then acts as a methyl group donor for the conversion
of homocysteine to methionine. This folate–cobalamin
interaction is pivotal for normal synthesis of
purines and pyrimidines, and therefore of DNA. The
methionine synthetase reaction is largely responsible for
the control of the recycling of folate cofactors; the maintenance
of intracellular concentrations of folylpolyglutamates;
and, through the synthesis of methionine and its
product, S-adenosylmethionine, the maintenance of a
number of methylation reactions.
Because methyltetrahydrofolate is the principal
folate congener supplied to cells, the transfer of the
1087
CHAPTER 37
HEMATOPOIETIC AGENTS
Plasma
CH 3 H4PteGlu 5
CH 3 H 4 PteGlu 1 CH 3 H 4 PteGlu 1 H 4 PteGlu
B 12 -TcII
TcII
Cell
?
CH 3 B 12
Homocysteine
Methionine
B 12
Deoxyadenosyl B 12
FIGLU
Serine
H 2 PteGlu
+B6
DNA
dUMP
(Deoxyuridylate)
dTMP
(Thymidylate)
5,10-CH 2 H 4 PteGlu
Glycine
5,10-CHH4PteGlu
5-CHOH4PteGlu
Purine
Synthesis
?
10-CHOH 4 PteGlu
Methylmalonyl
CoA
Succinyl
CoA
Glutamic
acid
5-CHNHH 4 PteGlu
Figure 37–6. Interrelationships and metabolic roles of vitamin B 12
and folic acid. See text for explanation and Figure 37–7 for
structures of the various folate coenzymes. FIGLU, formiminoglutamic acid, which arises from the catabolism of histidine; TcII,
transcobalamin II; CH 3
H 4
PteGlu 1
, methyltetrahydrofolate.