Liver cytotoxic

The liver is a major target organ because of factors (i), (n), (iv), and (vii). The main effects are fatty liver, cytotoxicity (necrosis), cholestasis, cirrhosis, and tumors. 

The liver shows the following types of toxic response steatosis (fatty liver), cytotoxic damage, cholestatic damage, cirrhosis, vascular lesions, liver tumors, and proliferation of peroxisomes. 

Mitomycin C, an antibiotic produced by fermentation of streptomyces, has been used extensively in Japan for the treatment of stomach cancer which is prevalent in that country. It probably acts after conversion into an alkylating agent in vivo, and it also contains quinone and urethane moieties which may contribute to its anti-tumour effect. A related series of compounds, the pyrol-lizidine alkaloids, occur in a variety of plants and are known to cause acute liver cytotoxicity when accidentally ingested93). Like mitomycin C, these agents are almost certainly metabolised in vivo by liver microsomes to alkylating agents which cause the liver toxicity. Some of these alkaloids have antitumour properties, presumably because the active metabolite formed in the liver is stable enough to reach the tumour. 

Supporting data from studies in isolated rodent tissues and the standard geno-toxicity assays in Salmonella and other species can help inform the mechanistic interpretations. However, a risk assessor must evaluate these data with caution. Are the results from liver (where regenerative hyperplasia is most often observed) relevant to tumors that may be observed in other organs If a chemical caused tumors in liver, bladder, and lung, for example, but correlative cytotoxicity was only documented in liver, what should be concluded from the liver cytotoxicity data The data may seem solid for a cytotoxic threshold for liver tumors in rats, while kidney tumors are observed without notable renal cytotoxicity in mice, and a genotoxic metabolite is detected. In this case, a cautious risk assessor would not likely conclude that a nonlinear extrapolation is appropriate for determination of a regulatory standard, based on the mouse data. 

Maximal tolerated dose, or a dose inducing liver cytotoxicity (e.g., pyknotic nuclei) or 2000mg/kg/day. 

In vitro cytotoxicity assays using isolated cells have been applied intermittently to cyanobacterial toxicity testing over several years." Cells investigated for suitability in cyanobacterial toxin assays include primary liver cells (hepatocytes) isolated from rodents and fish, established permanent mammalian cell lines, including hepatocytes, fibroblasts and cancerous cells, and erythrocytes. Earlier work suggested that extracts from toxic cyanobacteria disrupted cells of established lines and erythrocytes," but studies with purified microcystins revealed no alterations in structure or ion transport in fibroblasts or erythrocytes,... 

Changing the distribution of a drug can lead to toxic effects not described before. It is possible that after liposomal delivery high concentrations of drugs (e.g., cytotoxic drugs) inside macrophages affect these cells detrimentally (Poste and Kirsch, 1983). This results in toxic effects in liver, spleen, and bone marrow which were not previously associated with the use of these drugs. 

A considerable amount of the gold that accumulates in the kidneys and liver of mammalian species is bound to MTs. This buildup of gold in the kidneys is accompanied by elevated levels of renal copper to form copper-rich, gold-bearing MTs. In cell lines that overproduce MT, there is commonly a resistance to the cytotoxic effects of gold compounds. This resistance is also seen often in parent lines that have been repeatedly exposed to gold complexes. The mechanisms of resistance include but are not limited to enhanced biosynthesis of MT [102]. 

The identification and quantification of potentially cytotoxic carbonyl compounds (e.g. aldehydes such as pentanal, hexanal, traw-2-octenal and 4-hydroxy-/mAW-2-nonenal, and ketones such as propan- and hexan-2-ones) also serves as a useful marker of the oxidative deterioration of PUFAs in isolated biological samples and chemical model systems. One method developed utilizes HPLC coupled with spectrophotometric detection and involves precolumn derivatization of peroxidized PUFA-derived aldehydes and alternative carbonyl compounds with 2,4-DNPH followed by separation of the resulting chromophoric 2,4-dinitrophenylhydrazones on a reversed-phase column and spectrophotometric detection at a wavelength of378 nm. This method has a relatively high level of sensitivity, and has been successfully applied to the analysis of such products in rat hepatocytes and rat liver microsomal suspensions stimulated with carbon tetrachloride or ADP-iron complexes (Poli etui., 1985). 

Cytotoxicity of methylamine [45], kidney liver and myocardial damage due to ethylamine [46], hepatosplenomegaly and eosinophilia due to aniline [47], euphoria, dyspnea, teratogenicity, renal failure, hematuria, proteinurea, anorexia and methanoglobinemia due to a-naphthylamine and diphenylamine have been reported in the literature [48-54]. Therefore the remediation and mineralization of amines is... 

On the other hand, microsomes may also directly oxidize or reduce various substrates. As already mentioned, microsomal oxidation of carbon tetrachloride results in the formation of trichloromethyl free radical and the initiation of lipid peroxidation. The effect of carbon tetrachloride on microsomes has been widely studied in connection with its cytotoxic activity in humans and animals. It has been shown that CCI4 is reduced by cytochrome P-450. For example, by the use of spin-trapping technique, Albani et al. [38] demonstrated the formation of the CCI3 radical in rat liver microsomal fractions and in vivo in rats. McCay et al. [39] found that carbon tetrachloride metabolism to CC13 by rat liver accompanied by the formation of lipid dienyl and lipid peroxydienyl radicals. The incubation of carbon tetrachloride with liver cells resulted in the formation of the C02 free radical (identified as the PBN-CO2 radical spin adduct) in addition to trichoromethyl radical [40]. It was found that glutathione rather than dioxygen is needed for the formation of this additional free radical. The formation of trichloromethyl radical caused the inactivation of hepatic microsomal calcium pump [41]. 

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

Gardner, C.R., Wasserman, A.J., and Laskin, D.L., Liver macrophage-mediated cytotoxicity toward mastocytoma cells involves phagocytosis of tumor targets, Hepatology, 14, 318, 1991. 

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