PFPC
"Doses 1000x higher...."

REFERENCE SET:

LOW DOSES
© 1996 - 2016 PFPC

Note:
1 ppm
= 1mg/l
= 52.7 muM (μM), or mumol/L (μmol/L, micromoles, microM)
=0.0527 mM (millimoles)
Conversion Chart

  The ADA and many other pro-fluoride organizations claim that the concentrations of fluoride used in laboratory investigations studying effects on enzymes are "hundreds of times higher" than is present in body fluids or tissues. (The ADA, in its Fluoridation Fact booklet, uses a Hodge reference from 1965(!) to support this statement.). One review (ECUA 2000) even claims that levels are 1000 times higher.

    “Fluoride, in the amount provided through optimally fluoridated
    water, has no effect on human enzyme activity according to generally accepted scientific knowledge.” (
    ADA, 2005)

  The studies listed below are all done with micromolar levels of fluoride, and are only a small selection.

  To put the numbers in context:

  Normal fluoride levels in people using non-fluoridated water range from
0.25 to 2.20 mumol/L (Cowell & Taylor, 1980).

  Dental fluorosis occurs at chronic low plasma fluoride levels of 2 mumol/L and higher.

    "Chronic plasma fluoride levels in the range of 2-12
    mumol/L, attained by fluoride in drinking water for extended periods of time, induce disturbances in forming enamel in most species, including humans" (
    Bronckers et al, 2009)

  There are some laboratory studies showing effects of some fluoride compounds in the nanomolar range - and much LOWER than the levels known to produce dental fluorosis (Allmann et al, 1986; Misra et al, 2000).

==============

Allmann DW, Dunipace A, Jaouni S, Curro FA - "Stimulation of cAMP accumulation in rat aorta and diaphragm by fluorine containing compounds" Res Commun Chem Pathol Pharmacol 52(3):275-84(1986) (adenylyl cyclase pathway)

  • "Evidence is presented that accumulation of cAMP in isolated rat thoracic aorta and diaphragm is stimulated by several fluorine containing compounds (NaF, Na2PO3F (MFP) and SnF2). Time course experiments with NaF showed that maximal stimulation of cAMP accumulation was observed within 2.5 min. NaF and MFP produced significant increases in cAMP accumulation at concentrations of 0.1 microM and SnF2 produced a significant increase at 0.01 microM. The sensitivity of these tissues to the fluorine compounds is similar to that previously reported (Curro and Mickunas, 1981) for the inhibition of norepinephrine induced contractions by fluorine compounds in isolated thoracic aorta."

Anderson RE, Kemp JW, Jee WS, Woodbury DM - "Effects of cortisol and fluoride on ion-transporting ATPase activities in cultured osteoblastlike cells" In Vitro 20 (11):847-55 (1984) (10 μM)

Angmar-Mansson B, Ericsson Y, Ekberg O - "Plasma fluoride and enamel fluorosis" Calcif Tissue Res 22(1):77-84 (1976)

  • RATS: "... The results indicate that temporary peak values rather than elevated fasting values are responsible for the occurrence of enamel fluorosis and that the peak values must approach about 10 muM in order to block enamel formation by the ameloblasts. "

Arakawa Y, Bhawal UK, Ikoma T, Kimoto K, Kuroha K, Kubota T, Hamada N, Kubota E, Arakawa H - "Low concentration fluoride stimulates cell motility of epithelialcells in vitro" Biomed Res 30(5):271-7 (2009)

Baylink DJ - "Serum fluoride levels" In: Favus MJ, ed. Primers on the metabolic bone diseases and disorders of mineral metabolism, 2nd ed. New York: Raven Press; 262-263 (1993)

Bhawal UK, Lee HJ, Arikawa K, Shimosaka M, Suzuki M, Toyama T, Sato T, Kawamata R, Taguchi C, Hamada N, Nasu I, Arakawa H, Shibutani K - "Micromolar sodium fluoride mediates anti-osteoclastogenesis in Porphyromonas gingivalis-induced alveolar bone loss" Int J Oral Sci 18
(7):242-9 (2015)

  • "In our study, we found that 10 uM NaF significantly increased the apoptotic index of in vitro ameloblast-lineage cells."

Bronckers AL, Lyaruu DM, DenBesten PK - "The impact of fluoride on ameloblasts and the mechanisms of enamel fluorosis" J Dent Res 88(10):877-93 (2009)

Burgener D, Bonjour JP, Caverzasio J - "Fluoride increases tyrosine kinase activity in osteoblast-like cells: regulatory role for the stimulation of cell proliferation and Pi transport across the plasma membrane" J Bone Miner Res 10:164-171 (1995)

Caverzasio J, Imai T, Ammann P, Burgener D, Bonjour JP - "Aluminum potentiates the effect of fluoride on tyrosine phosphorylation and osteoblast replication in vitro and bone mass in vivo" J Bone Miner Res 11(1):46-55 (1996)

  • "We have found that minute amounts of Al (< or = 10(-5) M) potentiate the effects of F in vitro such that osteoblast proliferation increased by 15 +/- 2.7% at 50 microM (p < 0.001) and by 117.6 +/- 5.1% at 750 microM (p < 0.001), concentrations of F with no mitogenic effect alone... The results suggest that the combination of F + Al modulates a growth factor-dependent TyrP pathway enhancing mitogen-activated protein kinase and osteoblastic proliferation and bone mass”

Clark OH, Gerend PL - "Thyrotropin regulation of adenylate cyclase activity in human thyroid neoplasms" Surgery 97 (5):539-46 (1985)

Cornelius F, Mahmmoud YA, Toyoshima C - "Metal fluoride complexes of Na,K-ATPase: characterization of fluoride-stabilized phosphoenzyme analogues and their interaction with cardiotonic steroids" J Biol Chem. 286
(34):29882-92 (2011)

Curran TM, Buckley DH, Marquis RE - "Quasi-irreversible inhibition of enolase of Streptococcus mutans by fluoride." FEMS Microbiol Lett 119(3):283-8 (1994)

  • "Fluoride at concentrations greater than 0.01 mM was found to be a quasi-irreversible inhibitor of enolase of permeabilized cells of Streptococcus mutans GS-5 and also of isolated yeast enolase. The inhibition appeared to be of the type that has been described for P-ATPases, but was not dependent on added Al3+ or Be2+ ions."

de la Sota M, Puche R, Rigalli A, Fernandez LM, Benassati S, Boland R - "Changes in bone mass and in glucose homeostasis in subjects with high spontaneous fluoride intake" Medicina (B Aires) 57(4):417-20 (1997)

  • "... This observation coincides with experiments published elsewhere indicating that fluoride intake at concentrations 5 microM or greater, inhibits the secretion of insulin."

DenBesten PK, Yan Y, Featherstone JD, Hilton JF, Smith CE, Li W - "Effects of fluoride on rat dental enamel matrix proteinases" Arch Oral Biol 47(11):763-70 (2002)

  • In the peptide assay, rMMP-20 activity was significantly reduced by concentrations of fluoride as low as 2 microM at pH 6, with no significant effect at pH 7.2. These in vitro assays show that micromolar concentrations of fluoride can alter metalloproteinase activity, particularly when the pH is reduced to 6.0.

Farley JR, Wergedal JE, Baylink DJ - "Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone forming cells" Science. 222:330-332 (1983)
(2 mumol) 

Guha-Chowdhury N, Clark AG, Sissons CH - “Inhibition of purified enolases from oral bacteria by fluoride” Oral Microbiol Immunol 12(2):91-7 (1997)
(range of 16 to 54 microM)

Gutowska I, Baranowska-Bosiacka I, Siennicka A, Telesiński A, Stańczyk-Dunaj M, Wesołowska T, Gąssowska M, Kłos P, Zakrzewska H, Machaliński B, Chlubek D, Stachowska E - "Activation of phospholipase A(2) by low levels of fluoride in THP1 macrophages via altered Ca(2+) and cAMP concentration" Prostaglandins Leukot Essent Fatty Acids 86(3):99-105 (2012)

  • "In macrophages cultured with NaF, concentration of cAMP significantly increased in a dose dependent manner (Fig. 1); 19% for 1 uM NaF (p=0.028), 71% for 3 uM NaF (p=0.027), 174% for 6 uM NaF (p=0.027) and 221% for 10 μM NaF (p=0.015)."

Gutowska I, Baranowska-Bosiacka I, Safranow K, Jakubowska K, Olszewska M, Telesiński A, Siennicka A, Droździk M, Chlubek D, Stachowska E - "Fluoride in low concentration modifies expression and activity of 15 lipoxygenase in human PBMC differentiated monocyte/macrophage" Toxicology 295(1-3):23-30 (2012)

  • "Additional 15LOX-2 expression in macrophages after fluoride addition was low in 1 and 3 μM concentrations, but increased significantly after 10 μM fluoride addition what may suggest developing acute inflammation, because 15LOX-2 is associated to increased local hypoxia."

Jenq SF, Jap TS, Hsieh MS, Chiang H - "The characterization of adenyl cyclase activity in FRTL-5 cell line." Chinese Medical Journal (Taipei) 51(3):159-65 (1993)

  • RATS: "Sodium fluoride stimulation study demonstrated dual actions of fluoride on adenylate cyclase; when the cells were assayed with increasing concentration of NaF, the AC activity increased as the concentration of NaF increased from 0.01 to 1 mM, but decreased strikingly as that concentration increased from 1 mM to 100 mM....
    When the concentration of nonhydrolyzable guanine nucleotide analogs increased in the presence of TSH, there was first an increase in adenylate cyclase activity, followed by a decrease at higher concentration." [Fisher rat thyroid cell line]

Kawase T, Ishikawa I, Orikasa M, Suzuki A -" Aluminum enhances the stimulatory effect of NaF on prostaglandin E2 synthesis in a clonal osteoblast-like cell line, MOB 3-4, in vitro." Biochem (Tokyo) 106(1):8-10 (1989)

  • " In the presence of 10 microM Al3+, NaF concentrations ranging from 0.01 to 1 mM increased PGE2 synthesis in a dose-dependent manner, though 10 microM Al3+ had no effect by itself. Similar effects were observed on alkaline phosphatase (ALP) activity per well, but a stimulatory effect of NaF on protein synthesis was observed only in the presence of 10 microM Al3+. These data demonstrated that PGE2 synthesis per protein was increased by NaF alone, and this effect was markedly enhanced by the addition of AlCl3. ALP activity per protein was, however, significantly increased by NaF in the absence of AlCl3. Taken together with our previous finding that Al3+ enhances the NaF-induced Ca2+ mobilization in MOB 3-4 cells, these results suggest that F- combined with Al3+ (i.e., AlF4-) is a more potent stimulator of PGE2 synthesis in cells than F- alone, and that the AlF4- -enhanced PGE2 synthesis may be caused by an increase in cytosolic free Ca2+ concentration during activation of the G protein by AlF4-."

Korkmaz O - "In vitro effects of sodium fluoride and sodium dichromate on dynamic properties of human erythrocyte membrane" Biophys Chem 83(2):111-20 (2000)

Lau KH, Goodwin C, Arias M, Mohan S, Baylink DJ - “Bone cell mitogenic action of fluoroaluminate and aluminum fluoride but not that of sodium fluoride involves upregulation of the insulin-like growth factor system.” Bone 30(5):705-11 (2002)

  • “The fluoroaluminate (AlF(4)(-)) ion and sodium fluoride (NaF) have previously been shown to be bone cell mitogens. This study sought to determine whether the bone cell mitogenic action of AlF(4)(-) and/or NaF would involve the insulin-like growth factor (IGF) regulatory system. We evaluated the effect of mitogenic doses of AlF(4)(-) and NaF on the mRNA levels and the protein level (in conditioned media [CM]) of several components of the IGF system (i.e., IGF-2, IGF binding protein [IGFBP]-4, and IGFBP-5) in human TE85 osteosarcoma cells. Aluminum fluoride (AlF(3)) was included for comparison. NaF, AlF(3), and AlF(4)(-), each at 50-100 micromol/L, increased [3H]thymidine incorporation in TE85 cells. Mitogenic concentrations of AlF(3) and AlF(4)(-): (1) increased the mRNA (up to twofold after 24 h treatment) and protein (in CM) levels (up to 2.5-fold after 48 h treatment) of IGF-2; (2) increased the mRNA level (twofold) and the protein level in CM (up to threefold) of stimulatory IGFBP-5; and (3) either reduced slightly or had no effect on the mRNA and protein (in CM) levels of the inhibitory IGFBP-4. Conversely, mitogenic concentrations of NaF had no significant effects on the protein (in CM) or mRNA level of IGF-2, IGFBP-4, or IGFBP-5. The addition of an inhibitory concentration of IGFBP-4 completely abolished the bone cell mitogenic activity of AlF(3) and AlF(4)(-) but not that of NaF. The findings of this study provide strong evidence that the bone cell mitogenic activity of AlF(4)(-) and AlF(3), but not that of NaF, is mediated by the upregulation of the IGF regulatory system.”

Lange AJ, Arion WJ, Burchell A, Burchell B- “Aluminum ions are required for stabilization and inhibition of hepatic microsomal glucose-6-phosphatase by sodium fluoride” J Biol Chem 261(1):101-7(1986)

Lau KH, Baylink DJ - "Molecular mechanism of action of fluoride on bone cells" J Bone Miner Res 13(11):1660-7 (1998)

Mendoza-Schulz A, Solano-Agama C, Arreola-Mendoza L, Reyes-Márquez B, Barbier O, Del Razo LM, Mendoza-Garrido ME - "The effects of fluoride on cell migration, cell proliferation, and cell metabolism in GH4C1 pituitary tumour cells" Toxicol Lett 190(2):179-86 (2009)

    “Cell migration, a behaviour stimulated by growth factors, was increased in cells treated with 2.4 micromol/L. At this fluoride concentration, changes in phosphorylation status of both cytoskeletal and cytosolic protein fractions, as well as in actin cytoskeletal arrangements were observed.”

Menoyo I, Rigalli A, Puche RC - "Effect of fluoride on the secretion of insulin in the rat" Arzneimittelforschung 55 (8):455-60 (2005)
(5-20 micromol/L) 

Misra UK, Gawdi G, Pizzo SV - "Beryllium fluoride-induced cell proliferation: a process requiring P21(ras)-dependent activated signal transduction and NF-kappaB-dependent gene regulation" J Leukoc Biol 71(3):487-94 (2000)

  • "We studied the effect of beryllium fluoride on murine peritoneal macrophages and determined its effects on signal transduction and geneticregulation. At low concentration (1-5 nM), BeF(2) caused an approximate twofold increase in [(3)H]thymidine uptake and cell number, but above 5 nM, it showed cytotoxic effects. BeF(2) increased cellular inositol (1,4,5)trisphosphate (IP(3)) and [Ca(2)(+)](i) about twofold. The rise in [Ca(2)(+)](i) occurred consequent to release from IP(3)-sensitive Ca(2)(+) stores and from influx, mainly via L-type channels. A significant increase in the levels of MEK1, ERK1, p38 MAPK, and JNK phosphorylation was observed in BeF(2)-exposed macrophages. The levels of NF-kappaB and CREB transcription factors and the proto-oncogenes c-fos and c-myc were also elevated significantly. Intracellular Ca(2)(+) chelation blocked the effect of BeF(2). We conclude that BeF(2) at low concentration exerts its mitogenic effects in peritoneal macrophages by elevating [Ca(2)(+)](i), which triggers the activation of p21(ras)-dependent MAPK signaling
    cascades. "
    Note: G/q 11

Naka T, Maruyama S, Nagao T, Takayama F, Maki J, Yasui T, Sakagami H, Ohkawa S - "Inhibition of branching morphogenesis of mouse fetal submandibular gland by sodium fluoride--protection by epidermal growth factor" In Vivo 19(2):327-34 (2005)

  • "At a lower concentration of NaF (< 2 microM), the branching morphogenesis was slightly enhanced, whereas at a higher concentration of NaF (4 - 8 microM), it was almost completely inhibited. The inhibitory effect of NaF at the higher concentration was abrogated by stimultaneous addition of epidermal growth factor (EGF), but not by 5alpha-dihydrotestosterone (DHT) or insulin-like growth factor(IGF). These data demonstrate that EGF can effectively reduce the cytotoxic activity of NaF at micromolar concentration."

Nakade O, Koyama H, Arai J, Ariji H, Takada J, Kaku T - "Stimulation by low concentrations of fluoride of the proliferation and alkaline phosphatase activity of human dental pulp cells in vitro" Arch Oral Biol 44(1):89-92(1999)

  • "Fluoride at micromolar concentrations significantly and dose-dependently stimulated [3H]thymidine incorporation into DNA in DP-1, DP-2 and TE-85 cells, with optimal effects around 50 microM, by 127 +/- 7%, 124 +/- 0.6% and 152 +/- 13.4%, respectively. To assess the potential influence of fluoride on cell differentiation, the effects of mitogenic concentrations on alkaline phosphatase activity were measured. Fluoride significantly increased the enzyme's activity in DP-1 and TE-85 by 177 +/- 12% and 144 +/- 12.3%. To evaluate the effect on extracellular-matrix synthesis, the synthesis of type I collagen was indirectly determined by an assay of procollagen type I c-peptide production. Fluoride significantly increased that production by 150 +/- 8.7% in TE-85, but not in either DP-1 or DP-2."--

Partanen S - "Inhibition of human renal acid phosphatases by nephrotoxic micromolar concentrations of fluoride" Exp Toxicol Pathol 54(3):231-7
(2002)

Psarros N, Feige U, Duschner H - “Interactions of micromolar concentrations of fluoride with Streptococcus rattus FA-1” Caries Res 24(3):189-97
(1990)

  • “Inhibition of the metabolic activities of bacteria by trace amounts of fluoride is manifested phenomenologically as changes in the pH gradient and/or the electrical potential between the cellular interior and the surrounding medium. These data were obtained from the intracellular/extracellular distribution of radioactivity labelled fluoride (18F), 5,5-dimethyloxazolidine-2,4-dione (14C), and tetraphenylphosphonium chloride (14C). When taken up from acidic media, trace concentrations of fluoride (1-100 microM) reduce the intracellular/extracellular pH gradient and affect the electrical potential across the cell membrane. The chromatographic fractionation of fluoride-charged bacterial homogenates showed that fluoride is attached to many proteins of the cytoplasm, the cell membrane, and to nonproteinaceous components of the cell wall. Lysozyme treatment synergistically affects the vulnerability of the bacteria to micromolar concentrations of fluoride.

Sawano H - "Presynaptic augmentation induced by NaF in sympathetic ganglion of bullfrog" Nippon Seirigaku Zasshi 52(11):363-73 (1990)

  • "The amplitude of the orthodromic compound action potential (CAP) evoked by preganglionic nerve stimulation was remarkably augmented with 10 microM NaF... Furthermore, it suggests that NaF probably acts on Gs-protein which activates adenylate cyclase at the presynaptic membrane. This resulted in a great increase in intracellular cAMP at the synaptic terminal and it triggered the Ca2(+)-increase."

Shahed AR, Miller A, Chalker D, Allmann DW - "Effect of sodium fluoride on cyclic AMP production in rat hepatocytes"J Cyclic Nucleotide Res 5(1):43-53 (1979)

Shahed AR, Miller A, Allmann DW - "Effect of fluorine containing compounds on the activity of glycolytic enzymes in rat hepatocytes" Biochem Biophys Res Commun 94(3):901-8 (1980)

  • “...However, as little as 0.05-0.15 mM NaF induced a significant increase in cAMP production. It was also found that NaF would alter the production of glucose in isolated rat hepatocytes. When hepatocytes from fed rats were incubated with 0.05-5 mM NaF there was an increase in amount of glucose released from endogenous sources. Also NaF resulted in a decrease in lactate and pyruvate production. Similarly NaF stimulated glucose production in hepatocytes from fasted rats. The maximal stimulation was observed with about 0.15-0.25 mM NaF. At NaF concentrations greater than 1.5 mM a decrease in glucose production was observed. It is concluded that NaF increases the level of cAMP and alters glucose metabolism in intact hepatocytes.”

Smith ER, Barker KL - “Effect of sodium fluoride on glucose-6-phosphate dehydrogenase activity in the rat uterus” Biochim Biophys Acta 451(1):223-37 (1976)

  • Intrauterine administration of 50 mumol of NaF to the ovariectomized mature rat causes a 2--3-fold increase in the total uterine glucose-6-phosphate dehydrogenase activity within 24 h. The response is characterized by a 4--6 h lag with a maximum effect from 24 to 36 h after a single treatment. Uterine glucose-6-phosphate dehydrogenase activity continues to increase with daily administration of NaF through 4 days. ...The action of NaF on this pathway most likely results from inhibition of the glycolytic enzyme, enolase, and increased pathway utilization may be the factor which controls enzyme synthesis. When given in combination with other known inducers of uterine glucose-6-phosphate dehydrogenase such as estradiol and NADP+, NaF acts synergistically. “

Suska M - “The effect of sodium fluoride on the adenine nucleotide pool in erythrocytes of Wistar rats” Int J Occup Med Environ Health 14(4):369-73 (2001)

Tachado SD, Akhtar RA, Zhou CJ, Abdel-Latif AA - “Effects of isoproterenol and forskolin on carbachol- and fluoroaluminate-induced polyphosphoinositide hydrolysis, inositol trisphosphate production, and contraction in bovine iris sphincter smooth muscle: interaction between cAMP and IP3 second messenger systems” Cell Signal 4
(1):61-75 (1992)

  • “...AlF4- (10 microM) induced a slow but progressive hydrolysis of PIP2, accompanied by parallel production of IP3, formation of PA, and contraction of the smooth muscle..“

Thomas AB, Hashimoto H, Baylink DJ, Lau KH - "Fluoride at mitogenic concentrations increases the steady state phosphotyrosyl phosphorylation level of cellular proteins in human bone cells" J Clin Endocrinol Metab 81(7):2570-8 (1996)

  • "In summary, we have shown for the first time that mitogenic concentrations (i.e. 50-200 mumol/L) of fluoride increased the steady state level of tyrosyl phosphorylation of at least 13 cellular proteins in human bone cells, and that the increases were relatively slow in onset and sustained."

Usuda K, Kono K, Dote T, Nishiura H, Tagawa T - "Usefulness of the assessment of urinary enzyme leakage in monitoring acute fluoride nephrotoxicity" Arch Toxicol 73 (6):346-51 (1999)

Wergedal JE, Lau KH - "Human bone cells contain a fluoride sensitive acid phosphatase: evidence that this enzyme functions at neutral pH as a phosphotyrosyl protein phosphatase." Clin Biochem 25(1):47-53 (1992)

Wergedal JE, Lau KH, Baylink DJ - "Fluoride and bovine bone extract influence cell proliferation and phosphatase activities in human bone cell cultures." Clin Orthop (233):274-82 (1988)

  • "Fluoride stimulated [3H]thymidine incorporation and specific activity of alkaline phosphatase in human bone cells and chick bone cells but not in human skin cells. Fluoride also stimulated the cell population doubling rate of the human bone cells with an optimum of approximately 20 mumol/L."


Willems HM, van den Heuvel EG, Castelein S, Buisman JK, Bronckers AL, Bakker AD, Klein-Nulend J - "Fluoride inhibits the response of bone cells to mechanical loading" Odontology 99(2):112-8 (2011) (10, 25, 50 uM NaF-)

Wu LW, Yoon HK, Baylink DJ, Graves LM, Lau KH - "Fluoride at mitogenic doses induces a sustained activation of p44mapk, but not p42mapk, in human TE85 osteosarcoma cells" Clin Endocrinol Metab 82(4):1126-35 (1997)

Yan Q, Zhang Y, Li W, Denbesten PK - "Micromolar fluoride alters ameloblast lineage cells in vitro" J Dent Res 86(4):336-40 (2007)

    "Fluoride had a biphasic effect on cell proliferation, with enhanced proliferation at 16 microM, and reduced proliferation at greater than 1 mM F...Flow cytometry showed that both 10 microM and 20 microM NaF significantly increased the apoptotic index of ameloblast-lineage cells." 

Zeng YY, Benishin CG, Pang PK - "Guanine nucleotide binding proteins may modulate gating of calcium channels in vascular smooth muscle. I. Studies with fluoride."J Pharmacol Exp Ther 50(1):343-51(1989)

     “F- (2.5-20 microM) produced a Ca++-dependent contraction"

Zhang Y, Yan Q, Li W, DenBesten PK - "Fluoride down-regulates the expression of matrix metalloproteinase-20 in human fetal tooth ameloblast-lineage cells in vitro" Eur J Oral Sci  114(Suppl 1):105-110 (2006)

Zhang Y, Li W, Chi HS, Chen J, DenBesten PK - "JNK/c-Jun signaling pathway mediates the fluoride-induced down-regulation of MMP-20 in vitro" Matrix Biol  26:633-641   (2007)

 

OTHER:

Gregory RB, Berry MN - "The characterization of perfluorosuccinate as an inhibitor of gluconeogenesis in isolated rat hepatocytes" Biochem Pharmacol 38(17):2867-72 (1989)

  • "Perfluorosuccinate (5 mM) inhibited gluconeogenesis from lactate by 80% and from pyruvate by 40%. Significant inhibition (up to 30%) occurred at a concentration of perfluorosuccinate of 50 microM."

Frolkis VV, Tanin SA, Gorban YN -"Age-related changes in axonal transport" Exp Gerontol 32(4-5):441-50 (1997)

  • "Small doses of sodium fluoride accelerated AT [axonal transport], and this correlated with a rise in cAMP levels in ventral roots. High doses of sodium fluoride decelerated AT more markedly in old rats... It was shown that anabolic hormones (sex steroids and thyroxine) accelerated AT in both adult and old rats..."

Mueller WM, Gregoire FM, Stanhope KL, Mobbs CV, Mizuno TM, Warden CH, Stern JS, Havel PJ - "Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes" Endocrinology 139(2):551-8
(1998)

Bollen M, Stalmans W - "Fluorine compounds inhibit the conversion of active type-1 protein phosphatases into the ATPMg-dependent form" Biochem J 255(1):327-33 (1988)

  • The modulator protein slowly converts the glycogen-bound protein phosphatase from liver, as well as its catalytic subunit, into an inactive form that requires protein kinase FA and MgATP for reactivation. The inactivation process could be completely prevented by addition of either 0.3 mM-NaF or 0.3 mM-phenylmethanesulphonyl fluoride (PMSF). The effectiveness of the proteinase inhibitor was not due to production of free fluoride. With the catalytic subunit a half-maximal effect of either fluorine compound was obtained at 25-50 microM.
     
  • The inactivation process was instantaneously blocked by the addition of NaF or PMSF at any moment during the incubation of the catalytic subunit with modulator. This fluoride effect was reversible. It did not result from a decreased affinity of modulator for the catalytic subunit. The use of analogues of PMSF showed that the fluorine atom was essential, but structural aspects were also an important determinant.
     
  • The relative efficiency of fluorine compounds in preventing the inactivation of the catalytic subunit by modulator corresponded to their relative potency as inhibitors of the phosphorylase phosphatase activity, but the latter effect required at least 20-fold higher effector concentrations. Incubation of the catalytic subunit with 10 mM-PMSF or -NaF caused an irreversible inhibition of the enzyme.
     
  •  It is possible to prepare stable complexes of catalytic subunit and modulator, either active or ATPMg-dependent. Both species displayed the same molecular size during gel filtration. The inactive complex could be reactivated by incubation with MgATP and protein kinase FA. NaF and PMSF increased the final extent of re-activation at limiting concentrations of the protein kinase."

Suyatna FD, Setiabudy R, Herwana E, Tjandra - "Butyrylcholinesterase and C5+ variant in a Javanese ethnic group in Indonesia" Int J Clin Pharmacol Ther 38
(7):339-44 (2000)

  • (50 microM -> Butyrylcholinesterase is an aspect of cholinesterase, an enzyme that breaks down acetylcholine to stop its action.)

Guha-Chowdhury N, Clark AG, Sissons CH - "Inhibition of purified enolases from oral bacteria by fluoride" Oral Microbiol Immunol 12(2):91-7 (1997)

  • "Enolase activity in strains of oral streptococci previously has been found to be inhibited by 50% (Ki) by fluoride concentrations ranging from 50 to 300 microM or more in the presence of 0.5 to 1.0 mM inorganic phosphate ions."

Loftenius A, Andersson B, Butler J, Ekstrand J - "Fluoride augments the mitogenic and antigenic response of human blood lymphocytes in vitro" Caries Res 33(2):148-55 (1999)

  • "It has been shown that fluoride, the agent responsible for reduction of dental caries worldwide and a recognized proliferative agent, is an adjuvant when given intragastrically to rats. Furthermore, plasma fluoride levels increase in humans after various fluoride treatments. The studies presented here show that fluoride also has the ability to affect the cells of the human immune system. This was tested by measuring the effect of sodium fluoride (NaF) on cytokine production by human whole blood cells stimulated in vitro. These studies revealed that NaF augments the human lymphocyte response from human blood to a mitogen (phytohemagglutinin, PHA) or a specific antigen (morbilli antigen from infected cells, MorbAg). The cytokine interferon-gamma (IFN-gamma), released from activated T and/or NK cells, was significantly (p<0.01) increased when whole blood cells were simultaneously incubated with 0.62 mmol/l NaF and PHA compared to PHA alone. This tendency was also true for NaF and MorbAg. The lymphocyte activation marker interleukin-2 receptor (measured in soluble form) increased after simultaneous stimulation of the cells with PHA and 0.62 mmol/l NaF compared to stimulation with PHA only. However, 0.62 mmol/l NaF did not enhance interleukin-6 release, in blood mainly produced by monocytes. The ability to influence the IFN-gamma release during an immune response could be one of the primary means by which the fluoride ion influences the immune system.

see also:

Butler JE, Satam M, Ekstrand J - "Fluoride: an adjuvant for mucosal and systemic immunity" Immunol Lett 26(3):217-20 (1990)

  • "Fluoride, the agent responsible for reduction of dental caries worldwide, and a recognized proliferative agent, is a potent adjuvant when given intragastrically to rats. Intragastric fluoride causes increases in the size and cellularity of the Peyer's patches and mesenteric lymph nodes as well as the number of plasma cells secreting IgG and IgA antibodies to ovalbumin given in their drinking water. Rats ingesting NaF and fed OA showed a significant increase in surface immunoglobulin expression on lymphocytes from the Peyer's patches and mesenteric lymph nodes. The frequency of CD4+ T cells in these lymphoid tissues was elevated while that of CD8+ T cells was significantly decreased. In separate experiments, rats parenterally immunized with myelin basic protein (MBP) and fed NaF twice weekly, had significantly elevated serum IgG antibody activity to MBP compared to similarly immunized rats not receiving NaF. The supplemental fluoride prescribed for infants and especially that which is inadvertently ingested by children and adults given fluoride gels, is within the concentration range of that which produced the effects we observed in rats. The adjuvant effect we describe thus has relevance for fluoride therapy worldwide. "

======================================

Cowell DC, Taylor WH -"Ionic fluoride: a study of its physiological variation in man" Ann Clin Biochem 18
(Pt 2):76-83 (1981)

Pietkiewitz J, Bednarz-Misa I, Jermakow K, Gamian A - “Enolase from Klebsiella Pneumoniae and Human Muscle Cells II. Kinetic Parameters and Sensitivity to Fluoride and Phosphate Inhibitors” Adv Clin Exp Med 8(3):221–233
(2009)
http://www.advances.am.wroc.pl/pdf/1142.pdf

Zimmer S, Jahn KR, Barthel CR - "Recommendations for the use of fluoride in caries prevention"Oral Health Prev Dent 1(1):45-51 (2003)

 

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