Necrosis liver, compounds causing

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). 

Brodie, B.B. et al. 1971. Possible mechanism of liver necrosis caused by aromatic organic compounds. Proc. Natl. Acad. Sci. USA 68 160. 

Many toxic compounds cause direct damage to the hepatocytes, which leads to cell death and necrosis. This is a general toxic response, not specific for the liver, and there are undoubtedly many mechanisms, which underlie cytotoxicity, but most are still poorly understood. The mechanisms underlying cytotoxicity in general are discussed below, and several examples of hepa to toxins are discussed in more detail in chapter 7. 

Other compounds cause liver necrosis because of biliary excretion. Thus, the drug furosemide causes a dose-dependent centrilobular necrosis in mice. The liver is a target as a result of its capacity for metabolic activation and because furosemide is excreted into the bile by an active process, which is saturated after high doses. The liver concentration of furosemide therefore rises disproportionately (chap. 3, Fig. 34), and metabolic activation allows the production of a toxic metabolite (Fig. 6.6). The drug proxicromil (chap. 5, Fig. 11) caused hepatic damage in dogs as a result of saturation of biliary excretion and a consequent increase in hepatic exposure. 

Hepatic Effects. Chromium(VI) has been reported to cause severe liver effects in four of five workers exposed to chromium trioxide in the chrome plating industry. Derangement of the cells in the liver, necrosis, lymphocytic and histiocytic infiltration, and increases in Kupffer cells were reported. Abnormalities in tests for hepatic dysfunction included increases in sulfobromophthalein retention, gamma globulin, icterus, cephalin cholesterol flocculation, and thymol turbidity (Pascale et al. 1952). In a cohort of 4,227 workers involved in production of stainless steel from 1968 to 1984, excess deaths were observed from cirrhosis of the liver compared to expected deaths (0/E=55/31.6) based on national rates and matched for age, sex, and calender time having an SMR of 174 with confidence limits of 131-226 (Moulin et al. 1993). No measurements of exposure were provided. Based on limited information, however, the production of chromium compounds does not appear to be associated with liver effects. As part of a mortality and morbidity study of workers engaged in the manufacture of chromium(VI) compounds (84%) and chromium(III) compounds (16%) derived from chromium(VI) in Japan, 94 workers who had been exposed for 1-28 years were given a complete series of liver function... 

Hydrazine s odor is ammonia-like or fishy and is detectable by smell at 1-10 ppm. Because hydrazine is a marked corrosive, it can cause chemical burns of the skin. Hydrazine vapors may cause irritation of the mucus membranes of the eyes, nose, throat, and respiratory tract. Inhalation of vapors can produce cough, dyspnea, and pulmonary edema. Eye exposure to vapors or liquid can result in conjunctivitis, corneal damage, and blindness. Other clinical effects include nausea, vomiting, tremors, dizziness, hype-rreflexia, seizures, hypotension, liver necrosis, methemoglobinemia, and hemolysis. The National Institute for Occupational Safety and Health recommends that the level of hydrazine in workplace air not exceed 0.03 parts of compound per million parts of air (0.03 ppm) for a 2 h period. The Occupational Safety and Health Administration (OSHA) limits the amount of hydrazine in workplace air to 1 ppm for an 8 h workday. The Environmental Protection Agency (EPA) requires that spills or accidental releases into the environment of 1 pound or more of hydrazine be reported to the EPA. 

CHRONIC HEALTH RISKS the dust of silver and its soluble compounds cause ar-gyria, the build-up of deposited silver in tissues, leading to gray-blue discoloration of eyes, skin, nasal septum, and throat may cause mild, chronic bronchitis necrosis of bone marrow, liver, and kidney may occur. 

As the dose of acetaminophen was increased, the incidence and severity of the liver necrosis in mice was increased ( ). However, an increase in toxicity would be expected to occur regardless of the mechanism of toxicity. Thus, the apparent correlation between the increase in covalent binding and the incidence of toxicity based solely on changes in the dose (12,17) is only trivial and does not indicate whether the toxicity is caused by the parent compound, the chemically reactive metabolite or some other metabolite. 

The finding that cysteine can prevent the liver necrosis caused by acetaminophen in mice (17) led to the possibility that thio compounds might be useful as antidotes, provided that they are administered while the acetaminophen is being metabolized. Unfortunately, cysteine is a rather ineffective antidote except when it is administered intraperitoneally because it is incorporated into protein by all tissues of the body and thus is subject to a kind of first pass effect by these tissues. Most of the emphasis, therefore, has been toward the development of antidotes that serve as precursors of cysteine (such as methionine and N-acetylcysteine) and thus of glutathione or as alternative nucleophiles that combine with the chemically reactive metabolite. 

Hepatotoxicity does not occur at recommended doses of acetaminophen. Administration of 2 g, or twice the recommended dose, of intravenous paracetamol in healthy subjects has been shown to stay far below the threshold of hepatotoxicity. When ingested at high doses, acetaminophen is metabolized to JV-acetyl-p-benzoquinone-imine (NAPQI). NAPQI is rapidly conjugated with glutathione to a nontoxic compound. The depletion of glutathione results in the accumulation of NAPQI that is responsible for liver injury. Acetaminophen has a narrow therapeutic window and even minor overdoses may cause severe hepatic injury. Liver necrosis occurs at 7.5-10 g of acetaminophen. 

Acute Liver Damage Several compounds (e.g., dimethyl iiitrosoamine, carbon tetrachloride, and thioacetamide) cause necrosis of hepatocytes by inhibiting pro tein syndiesis at the translational level, i.e., by inhibiting the addition of new amino adds into the protein chain being sjTithetized. This is not, however, the only mechanism. Ethioiiine is a compound which inhibits protein synthesis bur doe not induce... 

Balb c mice and Wistar rats were used in the experiments. The administration of single doses of 1, 2 and 2 caused mainly necrotic changes in the liver, measured by GPT and histopathology. The extent of necrosis depended on doses and on time of observation (1-4 days after injections). In shorter time interval (2-4 hrs) 1, 2 and 2 caused depletion of hepatic GSH (even up to 10 % of control). 4 and 5 did not generate necrotic changes. Increased GPT activity was observed after 3 doses of fi. Single doses of 4, 5 and fi mostly increased the level of malondialdehyde (MDA-indicator of lipid peroxidation) in the liver. Repeated injections (3-7) of the investigated compounds enhanced the activity of ALA-D or ALA-S in the liver and caused steatosis. 

Rats fed diets containing 30 or 300ppm ammonium perfluorooctanoate for 2 years had increased liver weights with occasional necrosis and an apparent dose-dependent increase in Leydig cell adenomas, but there was no evidence of an increased incidence of hepatocellular carcinoma. In a follow-up study in male mice, 300ppm in the diet for 2 years caused increases in liver, Leydig cell, and pancreatic acinar cell tumors that may have been associated with the peroxisome-proliferating capabilities of the compound. Ammonium perfluorooctanoate also produced sustained increases in serum estradiol concentrations. ... 

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