Vitamin B6 occurs as an alcohol
(pyridoxine), an aldehyde (pyridoxal), and an amine (pyridoxamine).
These forms are phosphorylated in the 5'-position to produce the
physiologically active coenzymes that are critical to their biological
function. Eukaryotes cannot synthesize vitamin B6 molecules from smaller compounds and as a result require dietary B6
for the synthesis of 5'-phosphate vitamins. Pyridoxal 5'Phosphate
(PLP), the most clinically significant coenzyme form of vitamin B6, is the form most commonly measured in plasma.1-3
PLP
serves as a coenzyme for more than 100 enzymes that catalyze key steps
in the metabolism of amino acids, neurotransmitters, nucleic acids,
heme, and lipids.1,4,5 Vitamin B6 is a critical cofactor for enzymes involved in energy homeostasis through glycogen degradation and gluconeogenesis.5
Inverse associations have been shown between plasma PLP and chronic or
acute disease, including rheumatoid arthritis, cardiovascular disease,
deep vein thrombosis, and cancer.4-16 A number of
epidemiologic studies have shown reduced concentrations of circulating
PLP in association the acute phase marker C-reaction protein13-17 and with inflammatory markers.18-19 Diminished vitamin B6
levels are frequently observed without any indication of a lower
dietary intake or excessive catabolism of the vitamin, or congenital
defects in its metabolism.4 Research is ongoing to determine if these lower vitamin B6 levels are caused by the mobilization of this coenzyme to the site of inflammation for use by the PLP-dependent enzymes4 or due increased catabolism of vitamin B6 during inflammation.5
PLP serves as a coenzyme for d-aminolevulinate synthase, which catalyzes the first step in heme biosynthesis.1,5 B6
deficiency can produce a hypochromic form of anemia characterized by
the presence of ring sideroblasts (iron positive granules deposited
about the nucleus of red cell precursors). Occasionally the anemia may
have megaloblastic characteristics. Inherited abnormalities of
apoenzymes that bind with pyridoxal phosphate are responsible for
newborn conditions characterized by mental retardation, skeletal
deformities, thrombotic conditions, osteoporosis, and visual defects.
Some inherited abnormalities of vitamin B6 metabolism and transport are associated with aminoacidurias including homocystinuria, hypermethioninemia, cystathioninuria.21
A number of studies have demonstration an inverse association between
plasma PLP levels and the risk of developing colorectal cancer.20
A recent meta- analysis indicated that the risk of developing this type
of cancer decreased by 49% for every 100-pmol/mL increase in blood PLP
level.20
Vitamin B6 deficiency can occur in individuals with a variety of genetic conditions including antiquitin deficiency,21 pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency22 and hyperprolinemia type II (pyrroline-5- carboxylate dehydrogenase deficiency.23 Vitamin B6
levels can be decreased in malabsorption conditions including
inflammatory disease of the small bowel and as a consequence of
jejunoileal bypass.4,5 Several drugs, including oral contraceptive agents, levodopa, isoniazid, cycloserine, and pyrazinoic acid may cause B6 depletion.1 B6 levels may be decreased with pregnancy, lactation and alcoholism.1 Infants can develop deficiency when fed formula rendered B6 depleted by excessive heating.
Markedly
elevated plasma PLP levels are observed in cases of hypophosphatasia
(HPP), an inborn error of metabolism caused by a loss-of-function
mutation(s) within the gene for the cell surface enzyme, tissue
nonspecific isoenzyme of alkaline phosphatase (TNSALP).24-28
This disorder is characterized by low serum alkaline phosphatase
activity and increased plasma levels of TNSALP substrates including
inorganic pyrophosphate, phosphatidylethanolamine and PLP. Clinical
features can include childhood rickets, adult osteomalacia and dental
abnormalities. These symptoms are thought to occur as a result of the
accumulation of inorganic pyrophosphate which inhibits hydroxyapatite
crystal formation and growth, leading to defective skeletal and dental
mineralization. PLP, carried in the plasma on albumin, must be
de-phosphorylated by TNSALP for pyridoxal to cross cell membranes. Once
inside the cell, the pyridoxal is regenerated as PLP to allow it to
function as a coenzyme. The diminished TNSALP of individuals with HPP
leads to an accumulation of the PLP substrate in plasma. HPP patients do
not typically experience B6 related symptoms. However, the extent of PLP elevation has been related to the disease severity.28
