Dietary nickel and folic acid interact to affect folate and methionine metabolism in the rat.

A previous experiment using rats indicated that dietary nickel (Ni), folic acid, and their interaction affected variables associated with one-carbon metabolism. That study used diets that produced only mild folate deficiency. Thus, an experiment was performed to determine the effect of a severe folate deficiency on nickel deprivation in rats. A 2 x 2 factorially arranged experiment used groups of six weanling Sprague-Dawley rats. Dietary variables were nickel, as NiCl2-6H2O, 0 or 1 microgram/g and folic acid, 0 or 4 mg/kg. All diets contained 10 g succinylsulfathiazole/kg to suppress microbial folate synthesis. The basal diet contained < 20 ng Ni/g. After 58 d, an interaction between nickel and folate affected the urinary excretion of formiminoglutamic acid (FIGLU) and the liver concentration of S-adenosylmethionine (SAM). Because of this, it is proposed that the physiological function of nickel is related to the common metabolism shared by SAM and FIGLU. Possibly the physiological function of nickel could be related to the tissue concentration of 5-methyltetrahydrofolate (MTHF) or tetrahydrofolate (THF).

Dietary folate affects the response of rats to nickel deprivation.

Because vitamin B12 and Ni are known to interact and because of the similar metabolic roles of vitamin B12 and folate, an experiment was performed to determine the effect of dietary folate on Ni deprivation in rats. A 2 x 2 factorially arranged experiment used groups of nine weanling Sprague-Dawley rats. Dietary variables were Ni, as NiCl(2) 6H(2)0, 0 or 1 mu g/g; and folic acid, 0 or 2 mg/kg. The basal diet, based on skim milk, contained less than 20 ng Ni/g. After 54 d, an interaction between dietary Ni and folate affected several variables including erythrocyte folate, plasma amino acids, and femur trace elements. For example, folate deprivation decreased erythrocyte folate; folate supplementation to the Ni-supplemented rats caused a larger increase in erythrocyte folate concentration than did folate supplementation to the Ni-deprived rats. Also, dietary Ni affected several plasma amino acids important in one-carbon metabolism (e.g., Ni deprivation increased the plasma concentrations of glycine and serine). This study shows that dietary Ni, folate, and their interaction can affect variables associated with one-carbon metabolism. This study does not show a specific site of action of Ni but it indicates that Ni may be important in processes related to the vitamin B12-dependent pathway in methionine metabolism, possibly one-carbon metabolism.

Effect of nitrous oxide on nickel deprivation in rats.

Because nickel may have a biological function in a pathway in which vitamin B12 is important, an experiment was performed to determine the effects of nitrous oxide exposure in rats deprived of nickel. Exposure to nitrous oxide (N2O) causes inactivation of cobalamin and a subsequent decrease in the vitamin B12-dependent enzymes methionine synthase and methylmalonyl CoA mutase. Rats were assigned to dietary groups of 12 in a factorially arranged experiment with dietary variables of nickel (0 or 1 microgram/g) and vitamin B12 (0 or 50 ng/g). After 6 wk, one-half of the rats from each dietary group were exposed to 50% N2O/50% O2 for 90 min/d for the last 28 d of the experiment. Vitamin B12, N2O, or their interaction had numerous effects; classical findings included N2O-induced reduction in plasma vitamin B12 and decreases in the vitamin B12-dependent enzymes. Inactivation of vitamin B12 by N2O, however, did not exacerbate signs of nickel deprivation, possibly because the rats were able to metabolically compensate to N2O exposure.

Dietary vitamin B12, sulfur amino acids, and odd-chain fatty acids affect the responses of rats to nickel deprivation.

An experiment was performed to ascertain whether changing the dietary intake of two substances, cystine and margaric acid (heptadecanoic acid), that affect the flux through pathways involving the two vitamin B12-dependent enzymes, methionine synthase and methylmalonyl-CoA mutase, would affect the interaction between nickel and vitamin B12. Rats were assigned to treatment groups of six in a fully crossed, four-factorial arrangement. The independent variables, or factors, were: per kg of fresh diet, nickel analyzed at 25 and 850 micrograms; vitamin B12 supplements of 0 and 50 micrograms; margaric acid supplements of 0 and 5 g; and L-cystine supplements of 0 and 12 g. The diet without cystine was marginally deficient in sulfur amino acids. Nickel affected growth, liver wt/body wt ratio (LB/BW), and a number of variables associated with iron, calcium, zinc, copper, and magnesium metabolism. Most of the effects of nickel were modified by the vitamin B12 status of the rat. In numerous cases, the interaction between nickel and vitamin B12 was dependent on, or altered by, the cystine or margaric acid content of the diet. Thus, the findings showed that the extent and the direction of changes in numerous variables in response to nickel deprivation varied greatly with changes in diet composition. These variables include those previously reported to be affected by nickel deprivation, including growth and the distribution or functioning of iron, calcium, zinc, copper, and magnesium. The findings also support the hypothesis that nickel has a biological function in a metabolic pathway in which vitamin B12 is important.