section 38.2
Water-Soluble Vitamins
917
enzymes are involved in transamination or decarboxyla-
tion of amino acids (Chapter 17). Under physiological
conditions, in the absence of apoenzymes, pyridoxal phos-
phate catalyzes similar reactions, but much more slowly
(by a factor of as much as
1 0
6) and without substrate
specificity.
Pyridoxine is synthesized by many plants and most
bacteria but not by higher animals. Principal dietary
sources are whole-grain cereals, wheat germ, yeast, meat,
and egg yolk. Bioavailability of dietary pyridoxine is
reduced by heat processing, possibly owing to reduc-
tion of Schiff base linkages between pyridoxal phosphate
and e-amino groups of lysine in proteins. Some infants
fed a formula that was heat-sterilized during prepara-
tion and inadequately fortified with vitamin Bg devel-
oped nervousness, irritability, and, in some cases, marked
opisthotonos.Administration of pyridoxine relieved these
symptoms. Rats and monkeys fed a vitamin Bg-dcficient
diet develop dermatitis and neuropathological changes.
The neurological symptoms seen with pyridoxine defi-
ciency in humans and animals may be due to decreased
synthesis of y-aminobutyric acid (GABA), a neurotrans-
mitter. Glutamate decarboxylase, which catalyzes the for-
mation of GABA from glutamic acid, requires pyridoxal
phosphate as a cofactor.
A pyridoxine requirement greater than normal has been
observed in patients with celiac disease, gastroenteritis,
and Crohn’s disease,presumably due to impaired intesti-
nal absorption. Increased need for vitamin Bg is observed
in infections, uremia, severe burns, pregnancy, and lacta-
tion. Low circulating levels of pyridoxine occur in patients
with active gastric ulcers, gastritis, gastric carcinoma,
and benign gastric polyps.Isoniazid, used for treatment of
tuberculosis, reacts with pyridoxal phosphate to form a hy-
drazone that is biologically inactive and also inhibits pyri-
doxal kinase and kynurenine transaminase. Deoxypyri-
doxine, a pyridoxine antagonist, produces symptoms of
vitamin Bg deficiency when administered to humans.
Vitamin Bg deficiency has been reported in rheumatoid
arthritis, some malignancies, liver disease, alcoholism,
diabetes mellitus,atherosclerosis,and some cases of hy-
perkinesisin children. At least seven inherited disorders
responsive to pharmacological doses of pyridoxine have
been described (Table 38-1).
Vitamin Bg status can be evaluated by direct mea-
surement of plasma pyridoxine or pyridoxal phosphate
by microbiological, enzymatic, radioimmunological, or
chemical methods. Measurement of urinary xanthurenic
acid or other intermediates of the kynurenine pathway
(Chapter 17) are used to assess indirectly the adequacy of
vitamin Bg for metabolic needs.
Vitamin Bg is rapidly absorbed from the intestine by
passive diffusion. Phosphorylated pyridoxine vitamers are
F IG U R E 3 8 -1 5
Metabolism of pyridoxine-related compounds in mammals. Enzymes: 1,
pyridoxal kinase (present in all mammalian tissues); 2, nonspecific
(probably alkaline) phosphatases; 3, pyridoxine oxidase (cofactor is FMN;
O
2
is required; subject to product inhibition); 4, aldehyde oxidase or
aldehyde dehydrogenase; 5, aminotransferase.
hydrolyzed by intestinal membrane alkaline phosphatase
before absorption.
For most enzymes, the coenzyme form of pyridoxine
is pyridoxal 5-phosphate. The transaminases can use
pyridoxamine
5-phosphate because they
interconvert
pyridoxal and pyridoxamine during their activity. The
three vitamers are readily converted to the active form
(Figure 38-15).
The predominant circulating form of vitamin Bg is pyri-
doxal phosphate. Absorbed pyridoxine is oxidized and
phosphorylated in intestinal mucosal cells, liver, and ery-
throcytes. Pyridoxine enters hepatocytes and erythrocytes
by passive diffusion and is mostly retained by phospho-
rylation. Pyridoxal phosphate is transported in the blood
bound to albumin. The blood-brain barrier has limited per-
meability to pyridoxal.
Pyridoxic acid is the principal urinary excretory form
of vitamin Bg when physiological doses of the vitamin are
given. Formation of pyridoxic acid is catalyzed by alde-
hyde oxidase or aldehyde dehydrogenase (Figure 38-15).
The FAD-dependent aldehyde oxidase seems to occur
only in liver, whereas the NAD+-dependent dehydroge-
nase is present in many tissues. Under physiological con-
ditions, the dehydrogenase is the more important enzyme.
Pyridoxal, pyridoxamine, and pyridoxine are excreted in
urine following pharmacological doses of vitamin Bg.
Only 2% of an intravenous dose of pyridoxine appears
in bile.
In rats and dogs, very high doses of pyridoxine cause
neurotoxicity characterized by demyelination of dor-
sal nerve roots, ataxia, and muscle weakness. Sensory
