Fatty liver, Lithium toxicology

 An example of a substance that causes steatosis(fatty liver) is valproic acid, once used as an anticonvulsant:

Other than ethanol, the xenobiotic chemical best known to cause steatosis is carbon tetrachloride, CCl4. This compound was once widely used in industry as a solvent, and even in consumer items as a stain remover. As discussed in some detail in Chapter 16, it is converted by enzymatic action in the liver to Cl3C· radical, then by reaction with O2 to Cl3COO· radical, which reacts with unsaturated lipids in the liver to cause fatty liver. 

Lithium can also be used to treat schizophrenia and some types of depression.

Lithium helps reduce feelings of mania — excited, high mood, distracted. It also helps to treat bipolar episodes.

Dimethylformamide is a xenobiotic industrial chemical known to cause liver cell death:

Reduced bile output can result in an accumulation of bilirubin, a dark-colored pigment produced by the breakdown of blood heme. When this product is not discharged at a sufficient rate with bile, it accumulates in skin and eyes, giving the characteristic sickly color of jaundice. Impaired production and excretion of bile is known as canalicular choleostasis. It can be caused by a number of xenobiotic substances, such as chlorpromazine. Reduced bile output can also result from damage to bile ducts.

Such concentrations have been known to cause deposition of substances such as sulfonamides and oxalates in the kidney, resulting in cell necrosis. Fortunately, the kidney has a good ability to compensate for damage

Toxic effects to the kidney may be manifested by acute and chronic renal failure. Many substances are known to be nephrotoxic. 14 Included among such substances are therapeutic agents. Some of these include organic mercury compounds administered as diuretics to increase urine output, anti-infective agents such as sulfonamides and vancomycin, antineoplastic (cancer therapeutic) adriamycin and mitomycin C, immunosuppressive cyclosporin A, analgesic and anti-inflammatory acetaminophen, and enflurane and lithium used to treat disorders of the central nervous system. A number of substances to which environmental and occupational exposure may occur have also been implicated in kidney damage. Some metals, including cadmium, lead, mercury, nickel, and chromium, are nephrotoxic. Some substances derived from bacteria (mycotoxins) and plants (especially alkaloids) are nephrotoxic. These include aflatoxin B, citrinin, pyrrolizidine alkaloids, and rubratoxin B. Nephrotoxic halogenated hydrocarbons include bromobenzene, chloroform, carbon tetrachloride, and tetrafluoroethylene, which is transported to the kidney as the cysteine S-conjugate. Ethylene glycol and diethylene glycol harm kidneys because of their bioconversion to oxalates that clog kidney tubules. Herbicidal paraquat, diquat, and 2,4,5-trichlorophenoxyacetate also have toxic effects on the kidney

Lithium, Li, atomic number 3, is the lightest group 1A metal that should be mentioned as a toxicant because of its widespread use as a therapeutic agent to treat manic-depressive disorders. It is also used in a number of industrial applications, where there is potential for exposure. The greatest concern with lithium as a toxicant is its toxicity to kidneys, which has been observed in some cases in which lithium was ingested within therapeutic ranges of dose. Common symptoms of lithium toxicity include high levels of albumin and glucose in urine (albuminuria and glycosuria, respectively). Not surprisingly, given its uses to treat manic-depressive disorders, lithium can cause a variety of central nervous system symptoms. One symptom is psychosomatic retardation, that is, retardation of processes involving both mind and body. Slurred speech, blurred vision, and increased thirst may result. In severe cases, blackout spells, coma, epileptic seizures, and writhing, turning, and twisting choreoathetoid movements are observed. Neuromuscular changes may occur as irritable muscles, tremor, and ataxia (loss of coordination). Cardiovascular symptoms of lithium poisoning may include cardiac arrhythmia, hypertension, and, in severe cases, circulatory collapse. Victims of lithium poisoning may also experience an aversion to food (anorexia) accompanied by nausea and vomiting

Lithium exists in the body as the Li+ ion. Its toxic effects are likely due to its similarity to physiologically essential Na+ and K+ ions. Some effects may be due to the competion of Li+ ion for receptor sites normally occupied by Na+ or K+ ions. Lithium toxicity may be involved in G protein expression and in modulating receptor–G protein coupling.

Lithium forms a very unstable carbonyl, for which the toxicity is suspected of being high. The formula of this compound is LiCOCOLi, written in this manner to show that the two CO molecules form bridges between two Li atoms. Unless otherwise known, the toxicities of lithium organometallic compounds should be regarded as those of lithium compounds and of organometallic compounds in general. The latter were discussed in Section 12.4. Lithium oxide and hydroxide are caustic bases, and they may be formed by the combustion of lithium organometallic compounds or by their reaction with water. Lithium ion, Li+, is a central nervous system toxicant that causes dizziness, prostration, anorexia, apathy, and nausea. It can also cause kidney damage and, in large doses, coma and death.

Beryllium Beryllium (Be) is in group 2A and is the first metal in the periodic table to be notably toxic. When fluorescent lamps and neon lights were first introduced, they contained beryllium phosphor; a number of cases of beryllium poisoning resulted from the manufacture of these light sources and the handling of broken lamps. Modern uses of beryllium in ceramics, electronics, and alloys require special handling procedures to avoid industrial exposure. Beryllium has a number of toxic effects. Of these, the most common involve the skin. Skin ulceration and granulomas have resulted from exposure to beryllium. Hypersensitization to beryllium can result in skin dermatitis, acute conjunctivitis, and corneal laceration. Inhalation of beryllium compounds can cause acute chemical pneumonitis, a very rapidly progressing condition in which the entire respiratory tract, including nasal passages, pharynx, tracheobronchial airways, and alveoli, develops an inflammatory reaction. Beryllium fluoride is particularly effective in causing this condition, which has proven fatal in some cases. Chronic berylliosis may occur with a long latent period of 5 to 20 years. The most damaging effect of chronic berylliosis is lung fibrosis and pneumonitis. In addition to coughing and chest pain, the subject suffers from fatigue, weakness, loss of weight, and dyspnea (difficult, painful breathing). The impaired lungs do not transfer oxygen well. Other organs that can be adversely affected are the liver, kidneys, heart, spleen, and striated muscles.

Hydrazine, is a common inorganic nitrogen compound. Hydrazine is hepatotoxic, causing accumulation of triglycerides in the liver, a condition commonly called fatty liver. These effects may be related to hydrazine’s ability to increase the activity of enzymes required to produce diglycerides, depletion of ATP, or inhibition of protein synthesis. Hydrazine acting in the liver induces hydrolysis of glycogen (animal starch) to release glucose, causing excessive blood glucose levels, a condition 

called hyperglycemia. This can result in depletion of glycogen, leading to the opposite effect, hypoglycemia. Hydrazine inhibits some enzymes, including phosphoenol pyruvate carboxykinase and some transaminases that are involved in intermediary metabolism. Swelling of cell mitochondria has been observed after exposure to hydrazine, and prolonged exposure can result in formation of large megamitochondria. The most serious toxicologic effect of hydrazine is its ability to indirectly cause methylation of DNA, leading to cancer. Inhalation of hydrazine has been linked to lung cancer.

Nitrite, NO2 – , administered intravenously as sodium nitrite solution or inhaled as amyl nitrite, C5H11NO2, an ester which hydrolyzes to NO2 – in the blood, functions as an antidote to cyanide poisoning. This occurs because nitrite oxidizes iron(II) in blood hemoglobin (HbFe(II)) to methemoglobin (HbFe(III)), a brown substance that is ineffective in carrying oxygen to tissues. (This reaction is the mechanism of nitrite toxicity; excessive formation of methemoglobin causes oxygen deprivation that can be fatal.) Methemoblogin in the blood, however, has a high affinity for cyanide and removes it from ferricytochrome oxidase enzyme that has been inhibited by binding of cyanide (Fe(III)-oxid–CN),

The evaporation of liquid ammonia in contact with flesh can cause frostbite. Ammonia is a potent skin corrosive and can damage eye tissue. When inhaled, ammonia causes constriction of the bronchioles. Because of its high water solubility, ammonia is absorbed by the moist tissues of the upper respiratory tract. Irritant damage to the lungs from ammonia can cause edema and changes in lung permeability.