# Mechanisms of Fluoride Toxicity: From Enzymes to Underlying Integrative Networks
## 4 The Implication of Fluoride Toxicity on Human Health
### The Potential Risk of Novel Fluorinated Drugs  
The advancements in organofluarine chemistry have increased the potential for the synthesis of fluorinated compounds used as novel drugs. These include general anesthetics, antibiotics, antiviral and antimalarial agents, anti-inflammatory drugs, antidepressants, antipsychotics, and different bio-compatible materials. Twenty percent of modern pharmaceuticals contain fluorine [163]. Fluorine substitution in a drug molecule influences not only its pharmacokinetic properties, such as absorption, tissue distribution, secretion, route and rate of biotransformation, but also its pharmacodynamics and toxicology. The fluorinated drugs are more potent; however, much less is known about the potential danger of these compounds for human health. We present some examples of fluorinated drug biotransformations, which could potentially contribute to the increasing burden of fluoride and evoke long-term health problems. Metabolic defluorination can readily occur, which favors the formation of stable fluoride ion, despite the strength of the C-F bond [163]. The highest defluorinating activity is characteristic of the liver, with the kidney, lungs, heart, and testicles in order of decreasing activity. The first of the modern fluorinated anesthetics halothane is metabolized by cytochrome P450 (CYP). In vitro investigations have identified a role for human CYPs 2E1 and 2A6 in oxidation and CYPs 2A6 and 3A4 in reduction [164]. The reductive pathway generates free radicals, which undergo further reduction and fluoride elimination. Oxidation produces trifluoroacetyl (TFA) chloride capable of covalently binding to proteins. TFA can either form trifluoroacetic acid, and be excreted with fluorine in urine, or form TFA adducts, which act as antigens in halothane-induced hepatitis [165]. Another well-known example of a fluorinated drug is cerivastatin, from the statin class. The awareness of muscular adverse drug reactions and fatal kidney failure led to the withdrawal of cerivastatin from the market in 2001 because of 52 deaths attributed to drug-related rhabdomyolysis [166]. Rhabdomyolysis is a syndrome caused by injury to skeletal muscle, which involves leakage of large quantities of potentially toxic intracellular contents into the blood plasma. This can lead to serious renal failure. Rhabdomyolysis was 10 times more common with cerivastatin than the other five approved statins. Laboratory and clinical investigations show that cerivastatin exerts direct pleiotropic effects on vascular endothelium and muscle fibers. It caused a significant membrane hyperpolarization, increased cGMP levels, and nitric oxide production in cultured human umbilical vein endothelial cells [167]. These data show that cerivastatin activates endothelial Ca\({}^{2+}\)-activated K\({}^{+}\) channels, which play an important role in the signaling of cerivastatin-mediated endothelial NO production and proliferation. Fluoroacetate is a rare naturally occurring organofluorine that is surprisingly poisonous. Biochemists found that the toxicity was due to the CH2F group [168]. In addition to mice, rats, guinea-pigs, and rabbits, the larger animals, cats, dogs, monkeys, goats, and horses were used for studies of its toxicity. Fluoroacetate was studied for potential use as a chemical weapon during World War II. Fluoroacetate is a simple molecule capable of inactivating the citric acid cycle with the substitution of a single hydrogen substituent for fluorine in the CH2F group (Figure 6). Despite understanding of the biochemical mechanism of fluoroacetate toxicity, an efficient antidote preventing the fluorocitrate synthesis has not been found. Surprisingly, ethanol, if taken immediately after the poisoning, has been the most efficient antidote [168]. Some fluorinated compounds--used as anticancer agents, narcotic analgesics, pesticides or industrial chemicals--metabolize to fluoroacetate as intermediate products. It was detected in the urine of oncologic patients with solid cancers treated with 5-fluorouracil (5-FU) [169; 170].