Vitamin B-6 and Hypophosphatasia
Soft Bones First Scientific Meeting
Decreased activity of tissue non-specific alkaline phosphatase (TNSALP) in hypophosphatasia (HPP) is associated with markedly increased concentrations of pyridoxal 5’-phosphate (PLP) in plasma. The plasma concentrations of pyridoxal (PL) and 4-pyridoxic acid remain normal in HPP which distinguishes it from increased dietary intake of vitamin B-6 which raises the plasma concentrations of all three vitamers. Organ ablation studies in dogs demonstrated that liver is the primary source of plasma PLP, probably secreted associated with albumin. The half-life of a 5 mg i.v. dose of PLP in normal humans is 2 to 3 h. Plasma PLP concentrations normally do not exceed 1000 nM presumably reflecting maximal production by the liver. During pregnancy in carriers of HPP plasma activity of placental ALP increases accompanied by a decline in plasma PLP concentration. PLP increases after delivery. While TNSALP is an exoenzyme, there appears to be a specific PLP phosphatase within the cell. As a result, there is little evidence of altered intracellular metabolism of vitamin B-6 in humans with HPP other than pyridoxine-dependent seizures in some neonatal and infant cases. Data from knockout mice suggest the seizures result from decreased gamma-aminobutyrate. In these mice i.p. PL was more effective than pyridoxine in prolonging survival. While plasma PL values remain normal in HPP patients, plasma PL and tissue B-6 vitamer concentrations are reduced in the knockout mice. Clinical assays for ALP usually use nonphysiological conditions and substrates. Under physiological conditions normal plasma concentrations of inorganic phosphate inhibit ALP about 50%. HPP may exhibit neuromuscular symptoms. About 75% of the vitamin B-6 in the body is associated with glycogen phosphorylase in muscle. We have not found any data on glycogen phosphorylase activity in HPP. We are developing a physiologically based pharmacokinetic model of vitamin B-6 metabolism which we hope will provide additional insights into vitamin B-6 metabolism in normal and pathological conditions.
vitamin B-6, hypophosphatasia
Biochemical Phenomena, Metabolism, and Nutrition | Musculoskeletal Diseases
Stephen P. Coburn, Karen Ericson, J D. Mahuren, and Douglas W. Townsend (2018).
Vitamin B-6 and Hypophosphatasia. Presented at Soft Bones First Scientific Meeting, Chicago, IL.