Vitamin B6 Dependence of One-Carbon Metabolism

Summary

Marginal vitamin B6 deficiency, which occurs commonly worldwide, leads to a cellular deficiency of the coenzyme pyridoxal phosphate (PLP). PLP is a coenzyme in several phases of one carbon (1C) metabolism, which is the array of reactions in which one carbon units are acquired and used in reactions including nucleotide synthesis, regeneration of methionine (Met) from homocysteine (Hcy), and methylation of many biological compounds. 1C metabolism is linked to the transsulfuration pathway in which Hcy undergoes PLP-dependent catabolism leading to cysteine, whose availability governs the formation of the antioxidant glutathione. Nutritional or genetic conditions that impair 1C metabolism are associated with elevation in plasma Hcy concentration and increased risk of vascular disease. It is believed that the metabolic effects of vitamin B6 deficiency will be most pronounced following protein intake when the vitamin B6-dependent pathways of amino acid metabolism experience the greatest substrate load. The human subjects protocols of this study consist of two distinct phases intended to extend our understanding of basic human 1C metabolism and the effects of marginal vitamin B6 deficiency under postprandial conditions. Phase 1 will investigate the effects of vitamin B6 nutrition on the PLP-dependent generation of 1C units by the glycine cleavage system and on the synthesis of glutathione. Phase 2 will investigate the dependence of methionine metabolism on vitamin B6 nutritional status, with particular emphasis on the recycling of Hcy to Met. Each phase of this study will involve 14 healthy, nutritionally adequate, young adults (7 male, 7 female) who will undergo metabolite profiling and kinetic analysis using intravenously infused stable isotopic tracers performed both before and after a \~4-week period of dietary vitamin B6 restriction. Subjects will be assigned to either Phase 1 or Phase 2, which will be identical in design except for the tracers and analytical methods used. We hypothesize that vitamin B6 deficiency will yield reduction in postprandial rates of homocysteine remethylation, generation of 1C units from glycine, and synthesis of glutathione. The results of this study will aid in assessing the consequences of nutritional and genetic variables affecting human metabolism and will further our understanding of the relationships between vitamin B6 nutrition and disease.

Conditions

• Vitamin B6 Deficiency

Interventions

DIETARY_SUPPLEMENT

Arm 1 glycine and leucine

Arm 1 glycine and leucine: A subset of 14 participants out of the total enrolled participants with an adequate nutritional status will undergo the tracer infusion of glycine and leucine amino acids protocol while an adequate vitamin pyridoxine, B6 status. After the first infusion each participant will then begin a diet low in vitamin B6 (\<0.5 mg/d) for 4 weeks to achieve marginal B6 status followed by a repeat of fasting blood sampling and tracer infusion protocol.

DIETARY_SUPPLEMENT

Arm 2 Intervention of Serine and methionine infusion

Arm 2 Intervention of Serine and methionine infusion: A subset of 14 participants out of the total enrolled participants. Received an adequate nutritional status will undergo the tracer infusion of methionine and serine amino acids protocol while in adequate vitamin pyridoxine, B6 status. After the first infusion each subject will then begin a diet low in vitamin B6 (\<0.5 mg/d) for 4 weeks to achieve marginal B6 status followed by repeat of fasting blood sampling and tracer infusion protocol.

Sponsors & Collaborators

• National Institutes of Health (NIH)

  collaborator NIH

• University of Florida

  lead OTHER

Principal Investigators

• Jesse F Gregory, PhD · University of Florida

Study Design

Allocation

NON_RANDOMIZED

Purpose

DIAGNOSTIC

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

20 Years

Max Age

40 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2008-01-31

Primary Completion

2010-09-30

Completion

2010-09-30

Countries

• United States

Study Locations