We have found that the induction of vitamin A deficiency in rats results in an adaptive response such that the flow of one-carbon compounds through the pool is primarily in the direction methionine synthesis rather than in the direction of carbon dioxide formation thus resulting in a redistribution of hepatic folate cofactors, notably a marked reduction of tetrahydrofolic acid. This adaptation occurs largely as the result of a marked decrease in N10formyltetrahydrofolate dehyrogenase and a marked increase in N5,10methylenetetrahydrofolate reductase, two key enzymes of the one-carbon pathway. We will first determine the time course of development of the effects of vitamin A deficiency on one-carbon metabolism and whether repletion with retinol or other retinoids will reverse the effects of the production of vitamin A deficiency. In addition we will determine if the effects of vitamin A deficiency on one-carbon metabolism which we have observed in liver are apparent in other rapidly dividing tissue such as testes, since studies from other laboratories have shown that testes are particularly susceptible to vitamin A deficiency. A second objective is to determine the metabolic reason for the marked change in enzyme activity in two key enzymes of the one-carbon pool due to vitamin A deficiency. Studies will be conducted to determine if actual changes in enzyme protein occur and/or if changes in levels of translatable mRNA coding for each protein occur, since studies by others have shown that genomic expression is altered as a result of vitamin A deficiency. To our knowledge, studies of this nature concerning the metabolic control of folate metabolism under any physiological condition have not been performed. Finally, our third major objective is to use the established methodology of tracer kinetic techniques to determine quantitatively the flow of one-carbon units through the folate dependent one-carbon pool under normal, physiological conditions and during the development of vitamin A deficiency. To date no quantitative measurements of flow through the pool have been made under any metabolic situation; therefore, the implementation of this methodology will significantly increase our ability to examine quantitative aspects of folic acid nutriture under a variety of situations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK035853-02
Application #
3234117
Study Section
Nutrition Study Section (NTN)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Earth Sciences/Resources
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Schalinske, K L; Steele, R D (1996) Carbon flow through the hepatic folate-dependent one-carbon pool is not altered in vitamin A-deficient rats. J Nutr 126:668-72
Schalinske, K L; Steele, R D (1996) Quantification of the carbon flow through the folate-dependent one-carbon pool using radiolabeled histidine: effect of altered thyroid and folate status. Arch Biochem Biophys 328:93-100
Schalinske, K L; Steele, R D (1996) Methotrexate alters carbon flow through the hepatic folate-dependent one-carbon pool in rats. Carcinogenesis 17:1695-700
Kaisaki, P J; Jerkins, A A; Goodspeed, D C et al. (1995) Cloning and characterization of rat cysteine sulfinic acid decarboxylase. Biochim Biophys Acta 1262:79-82
Schalinske, K L; Steele, R D (1993) 13-cis-retinoic acid and hepatic steatosis in rats. Biochem Pharmacol 46:319-25
Schalinske, K L; Steele, R D (1992) Variations in S-adenosylmethionine, S-adenosylhomocysteine and adenosine concentrations in rat liver. Biofactors 3:265-8
Schalinske, K L; Steele, R D (1991) 13-cis-retinoic acid alters methionine metabolism in rats. J Nutr 121:1714-9
Case, G L; Steele, R D (1989) Determination of reduced folate derivatives in tissue samples by high-performance liquid chromatography with fluorimetric detection. J Chromatogr 487:456-62
Schalinske, K L; Steele, R D (1989) Quantitation of carbon flow through the hepatic folate-dependent one-carbon pool in rats. Arch Biochem Biophys 271:49-55
Case, G L; Kaisaki, P J; Steele, R D (1988) Resolution of rat liver 10-formyltetrahydrofolate dehydrogenase/hydrolase activities. J Biol Chem 263:10204-7