Compounds Causing Liver Injury

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well- 

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Accumulation of lipids in the liver (steatosis) is one possible mechanism for liver toxicity. Several compounds causing necrosis of hepatocytes also cause steatosis. There are, however, some doubts that steatosis would be the primary cause of liver injury. Several compounds cause steatosis (e.g., puro-mycin, cycloheximide) without causing liver injury. Most of the accumulated lipids are triglycerides. In steatosis, the balance between the synthesis and excretion of these lipids has been disturbed (see Table 5.13). 

Many chemicals are hepatotoxic, including thousands of synthetic drugs and chemicals as well as a plethora of natural compounds such as bacterial, fungal, plant, and animal toxins. Some examples of chemicals causing liver injury are shown in Table 2. 

Trimethylene chlorohydrin is a moderately toxic compound. Ingestion can result in CNS depression, muscle contraction, gastrointestinal pain, and ulceration or stomach bleeding. High dosage can cause liver injury. The toxicity of this compound, however, is less severe than that of its isomer, propylene j6-chlorohydrin. 

For many compounds activation of the innate immune system has been shown to act as a deleterious amplification cascade that markedly exacerbates liver toxicity. In addition, some drugs have the ability to cause liver injury... 

Pessayre et al. (2012) and Mehta et al. (2008) describe the effects on mitochondria of more than a hundred compounds that cause liver injury, which are categorized by mechanism of action/target and provide an excellent data resource. 

Toxicology. Indium (In) and compounds cause injury to the lungs, liver and kidneys in animals. 

This is a chronic lesion resulting from repeated injury and subsequent repair. It may result from either hepatocyte damage or cholestatic damage, each giving rise to a different kind of cirrhosis. Thus, carbon tetrachloride will cause liver cirrhosis after repeated exposure, but also compounds, which do not cause acute necrosis, such as ethionine and alcohol may cause cirrhosis after chronic exposure. 

Toxicity Methylamine is known to cause irritation to eyes, nose, and throat in workers. Studies have indicated that the compound causes injury to eyes through corneal opacities and edema hemorrhages in the conjunctiva, and injury to liver.10 Studies of Guest and Varma33 indicated no significant deleterious effects on internal organs or skeletal deformities in experimental mice. 

In the previous sections, a number of chemicals that cause acute toxic liver injury have been reviewed in relation to their biochemical actions with or without tryptophan administration. It is of special interest that tryptophan was able to improve hepatic protein metabolism when administered before, simultaneously, or after administering the toxic compound (Table 6.2). Likewise, the effects of tryptophan on altered liver function due to the acute administration of selected drugs are reviewed. Overall, the experimental findings demonstrate that many of the regulatory effects of tryptophan on hepatic protein metabolism can occur even during acute liver injury. This raises many questions as to whether L-tryptophan may possibly have therapeutic applications under certain states of liver injury. Further experimental studies should establish whether this consideration is valid or not. 

This is often due to metabolites of a xenobiotic formed by bioactivation or biotransformation in the liver and not the parent compounds, and reactive metabolites are more likely to cause damage at the sites of phase I bioactivation reactions. Many different mechanisms cause hepatotoxicity and affect different cellular locations (Figures 3.3 and 3.4). Liver injury can be broadly classified as those injuries that are predictable and show a dose- and time-dependent pattern (type 1 lesions or intrinsic toxicity) and that occur in animals and are predictive of hepatic effects in man. Type... 

The toxicity of this compound is low. However, the acute toxic symptoms are those of ethylene and propylene chlorohydrins. Oral intake of this compound caused muscle contraction, gastrointestinal pain, ulceration, and liver injury in test animals. 

Methylene chloride is a low to moderately toxic compound, the toxicity varying with the animal species. It is less toxic in small animals than in humans. The toxic routes of exposure are inhalation of its vapors, ingestion, and absorption through the skin. It may be detected from its odor at a concentration of 300 ppm. Acute toxic symptoms include fatigue, weakness, headache, lightheadedness, euphoria, nausea, and sleep. High concentrations may produce narcosis. Rabbits exposed to 10,000 ppm for 7 hours died from exposure. The LC50 value in mice is 14,400 ppm/7 h (NIOSH 1986). Mild effects may be felt in humans from an 8-hour exposure to 500 ppm of methylene chloride vapors. Oral intake of 15-20 mL of the liquid may be lethal to humans. Chronic exposure to this compound can lead to liver injury. Contact of the liquid with skin or eyes can cause irritation. 

Thus chronic exposure to this compound can cause serious health hazard. The signs of toxicity in humans are headache, fever, profuse sweating, rapid pulse and respiration, cough, shormess of breath, and coma. Other symptoms noted are a decrease in hemoglobin, an increase in blood sugar, a loss of muscle tone, dyspnea, kidney and liver injury, and edema of the lung and brain. 

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