Microsomal necrosis

No changes in GTP and y-GT activity were recorded after repeated administration of the above compounds. Also, histopathological examination did not point to liver necrosis. Similar phenomenon detected earlier after repeated administration of monobromobenzene, was interpreted as a result of damage of the microsomal enzymatic system responsible for the appearance of active metabolites (ref. 22). 

Slater, T.F. (1968). The inhibitory effects in vitro of phenothia-zines and other drugs on lipid-peroxidation systems in rat liver microsomes, and their relationship to the liver necrosis produced by carbon tetrachloride. Biochem. J. 106, 155-160. 

Liver contained 156 (68-563) pg PCB 126/kg FW pronounced liver enlargement lymphoid depletion of spleen 10-fold increase in hepatic microsomal EROD and benzyoxyresorufin-O-dealkylase 5-fold increase in methoxyresorufin-O-dealkylase Liver had 380 pg PCB 126/kg FW with increasing necrosis above effects plus decreased bone growth, decreased spleen weight, and degenerative lesions of thyroid Liver had 1.1 (0.6-4.5) mg PCB 126/kg FW above effects plus decreased body weight, decreased hepatic thiol concentrations, and increased plasma enzyme activities... 

Liver necrosis is another concern following hexachloroethane exposure. Hexachloroethane is metabolized in the centrilobular area of the liver by way of the microsomal mixed function oxidase system. The relatively nonpolar pentachloroethyl free radical is an intermediate in this pathway. The reaction of the free radical with unsaturated lipids in the cellular or organelle membranes could contribute to hepatocyte damage and necrosis. 

The mechanism of toxification of isoniazid was investigated in rats pretreated with inducers or inhibitors of microsomal enzymes or an inhibitor of acylamidases. In animals pretreated with the acylamidase inhibitor bis(4-nitrophenyl) phosphate, isoniazid and acetylisoniazid produced less liver necrosis than in control animals. The treatment had no effect on the necrosis due to acetylhydrazine [173], In animals pretreated with inducers of microsomal cytochrome P450 such as phenobarbital, acetylisoniazid, and acetylhydrazine caused markedly increased necrosis, while pretreatment with cytochrome P450 inhibitors decreased necrosis. In contrast, the toxicity of isoniazid and hydrazine was not modified by phenobarbital pretreatment. From these observations, Trimbell et al. [173] concluded that the hydrolysis of acetylisoniazid is a prerequisite for hepatotoxicity, and that microsomal enzymes transform acetylhydrazine, the product of hydrolysis, to a toxic species. 

Determination of the level of cytosolic enzymes such as aspartate transaminase, alanine transaminase, and lactate dehydrogenase is part of standard biochemical liver function tests to measure hepatocellular necrosis [2, 101]. Cytosolic enzymes are not subject to genetic variations inherent in microsomal enzyme production. Liver cytosolic enzymes metabolize several molecules, of which galactose and amino acids are typical examples, used for hepatic function tests. 

Large oral doses of DDT in rats caused focal and centrilobular necrosis of the liver. However, in clinical evaluation and laboratory studies of 31 workers exposed to equivalent oral intakes of 3.6-18 mg daily for an average of 21 years, there was no evidence of hepatotoxicity an observed increase in activity of hepatic microsomal enzymes was not accompanied by clinical evidence of detriment to general health. ... 

Inhibitors of the microsomal enzymes decreased the covalent binding and the Clara cell necrosis and increased the LD50, even though the blood and pulmonary levels of ipomeanol... 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

Epoxidation and Aromatic Hydroxylation. Epoxidation is an extremely important microsomal reaction because not only can stable and environmentally persistent epoxides be formed (see aliphatic epoxidations, below), but highly reactive intermediates of aromatic hydroxylations, such as arene oxides, can also be produced. These highly reactive intermediates are known to be involved in chemical carcinogenesis as well as chemically induced cellular and tissue necrosis. 

Liver. In humans, chronic Cd exposure does not typically result in hepatotoxicity. In laboratory animals, the liver accumulates the largest concentrations of Cd after acute or chronic exposures. In chronically exposed rats, liver injury occurs prior to renal dysfunction. Chronic Cd effects in the liver include increased plasma activities of alanine and aspartate aminotransferases, structural irregularities in hepatocytes, and decreased microsomal mixed function oxidase and CYP450 activities. Acute exposures in rats result in hepatic necrosis, particularly in parenchymal cells. Additionally, rough endoplasmic reticulum deteriorates, while smooth endoplasmic reticulum proliferates. Mitochondria are also degraded. As is the case with chronic exposure, microsomal mixed function oxidases and CYP450s are inhibited. 

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