The fate of fluoride and the effect of fluoride upon glucose metabolism in intact rats Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/sn00b206w

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  • The inhibition of the enolase enzyme system by fluoride has been established for many years in in vitro experiments; however, this inhibitory action has never been demonstrated in an intact mammal. The present work was designed to examine the effect of fluoride administered by intravenous infusion in rats, under the assumption that enolase inhibition would be reflected in depressed glucose catabolism. Companion experiments were also carried out using ¹⁸F as a tracer to examine the time course of fluoride distribution in rats, thereby providing a better understanding of the over-all toxic action of fluoride. Radiorespirometric studies were carried out using ¹⁴C-labeled glucose to investigate the effect of fluoride upon glucose catabolism in intact rats. The results demonstrate that, when the concentration of administered fluoride builds up to 2x10⁻⁴ M on the basis of even distribution of fluoride in body fluid, significant inhibition of glucose catabolism occurs. Use was also made of ¹⁸F as a radiotracer of stable fluoride in the tissues of rats intravenously infused with various concentrations of fluoride. When fluoride was infused at a concentration of 0.126 M (2 mg fluoride per hour) the amount of fluoride accumulated in soft tissue was proportional to the cumulative amount of fluoride infused. The concentration of fluoride in soft tissue ranged from 10⁻⁴ to 10⁻³ M at a time which corresponded to the maximum fluoride inhibition of glucose catabolism seen in the radiorespirometric studies. The concentration of fluoride causing significant inhibitory effect on enolase in vitro, as reported in the literature, is on the order of 10⁻³ M. Two independent methods in the present study show that, when administered fluoride reaches a concentration of 10⁻⁴ to 10⁻³ M in blood and soft tissues, severe inhibition of glucose catabolism occurs in intact rats. Therefore, there is every reason to believe that one of the major toxic actions of fluoride in rats is due to the inhibition of the enolase system, a key step of glucose catabolism. Data obtained in ¹⁸F experiments in which 0.126 M fluoride was administered indicate that the fluoride in blood and soft tissues was promptly deposited in bone. Upon termination of fluoride administration, the major route of depletion of fluoride from blood andsoft tissues was by way of renal excretion, while fluoride incorporated into the bone remained at the same level without noticeable depletion over the period of these experiments. When ¹⁸F-labeled NaF was administered to rats at concentrations lower than 0.126 M, fluoride build-up in blood and soft tissues appeared to follow a similar pattern as that observed in 0.126 M fluoride experiments. In the ¹⁸F experiments it was also noted that, as the cumulative dose of fluoride administered by way of continuous infusion increased, there existed a defined ceiling in the capacity for fluoride removal by bone deposition or renal excretion. This resulted in excessive accumulation of fluoride in blood and soft tissues. It is is believed that the findings in the present work add much to the current understanding of fluoride toxicology in intact mammals. It is also noteworthy that a detailed description for preparation of ¹⁸F is presented in the present work, including several important revisions of previously published procedures.
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