Hepatotoxic compounds

Potential hepatotoxic effects of various brominated benzenes, however, should be considered. Bromobenzene which is a monobrominated compound, is used in various experiments as a model hepatotoxic compound (refs. 9-11). 

Drug-induced hepatotoxicity can present in variable manifestations, such as cell death (necrosis, apoptosis), infiammation, degeneration (steatosis), fibrosis/cirrho-sis and the development of tumors. The manifestations of drug toxicity may not be mutually exclusive and may occur sequentially, or in combination. ALT and ALP can be used to generally classify the pattern of liver injury as either hepatocellular (ALT >3x ULN), cholestatic (ALP >2x ULN, ALT/ALP <2) or mixed (elevated ALP and ALT). The successful monitoring of hepatotoxicity would identify cases before irreversible injury occurs. The activity levels of ALT, AST and ALP only increase after hepatic or cholestatic injury has occurred. Waiting for activity levels to exceed the established thresholds may be too late [3]. New biomarkers are needed to monitor/predict the specific sequence of events for different classes of hepatotoxic compounds. 

A great deal of information about hepatotoxicity has resulted from observed effects of pharmaceuticals, a number of which have been discontinued because of their damaging effects to the liver. An example of such a hepatotoxic compound tested as a pharmaceutical is fialuridine,... 

Hepatotoxins were isolated as new hepatotoxic compounds from the cyanobacterium Nostoc sp. strain 152 and assigned structures based on their high resolution FAB (fast atom bombardment) MS/MS, H and C NMR spectra, amino acid analysis and gas chromatography on a chiral capillary column by Namikoshi et al ... 

Figure 3 Halothane biotransformation. Approximately 80% of inhaled halothane is exhaled unchanged. The majority of the remaining 20% undergoes oxidative metabolism. This produces trifluoroacetic acid (TFA) as the major metabolite which is excreted in the urine, and smaller amounts of trifluoroacetyl chloride. The trifluoroacetyl chloride covalently binds to a variety hepatic proteins. Antibodies to these trifluoroacetylated proteins are thought to be a causative factor in the development of type II hepatotoxicity. Some reductive metabolism also occurs which involves the production of a free radical intermediate. It is believed that this intermediate is the hepatotoxic compound in type I hepatotoxicity. The metabolites chlorotrifluoroethane (CTF) and chlorodifluoroethylene (CDF) are exhaled and can serve as markers for reductive metabolism.

Hepatocytes show a remarkable heterogeneity and functional specialization which systematically differs depending on the cell s position in the lobule (simplified overview Fig. Id). For hepatotoxicity it is particularly relevant that many cytochrome P450 enzymes (e.g., CYP2E1 and CYP3A4) are preferentially expressed in the center of the lobule. Since many hepatotoxic compounds such as paracetamol or CC14 are metabolically activated by these enzymes they lead to a specific pericentral pattern of hepatotoxicity. 

Effect of L-Tryptophan before or after Treatment with Hepatotoxic Compounds or Drugs on Hepatic Protein Synthesis (Status of Polyribosomes and in Vitro Protein Synthesis)... 

Significant hepatoprotective activity of extracts of schisandra and compounds isolated from schisandra have been observed in mice, rats, and rabbits treated with hepatotoxic compounds (Hancke et al. 1999 Ko et al. 2002 Nakagiri et al. 2003 Zhu et al. 1999,2000). 

Studies in several laboratories have shown that strongly hepatotoxic cyclic heptapeptides of a common type occur in different strains of Microcystis [59]. Microcystis aeruginosa, the species most frequently investigated contains the peptide formulated in Fig. 25. The two letter suffix LA designates the two L-amino acids in positions 2 and 4 (X, Y = Leu, Ala) which have been found variable in all of the toxins examined to date. X can also be arginine (R) or methionine (M). The 10-carbon chain jS-amino acid is unique for this type of hepatotoxic compound. Another not quite common structural element is the unsaturated side chain of dehydroalanine (No. 7), the formation of which can readily be imagined by elimination of H2O from serine or H2S from cysteine. 

Many other bisben2ylisoquinoliae alkaloids, such as tetrandriae (80), from Cjcleapeltata Hook., are also known. Compound (80), for example, although it causes hypotension and hepatotoxicity ia mammals, ia other tests, possessed enough anticancer activity to be considered for preclioical evaluation (55). The arrow poison tubocurare prepared from Chondrendendron spp. also contains the bisben2yhsoquiQoline alkaloid tubocurariae (9). 

Liver cancer can also be a consequence of exposure to hepatotoxic chemicals. Natural hepatocarcinogens include fungal aflatoxins. Synthetic hepato-carcinogens include nitrosoamines, certain chlorinated hydrocarbons, polychlorinated biphenyls (PCBs), chloroform, carbon tetrachloride, dimethyl-benzanthracene, and vinyl chloride.Table 5.15 lists the chemical compounds that induce liver cancer or cirrhosis in experimental animals or... 

The effects of leukotrienes can be blocked at several levels. Inhibitors of FLAP or 5-LO inhibit LT synthesis at all levels. However, FLAP antagonists developed to date have been too hepatotoxic for human use. Zileuton, a 5-LO synthase inhibiting drug, also demonstrated some hepatotoxicity in a small percentage of patients, which was nonetheless entirely reversible. However, the short half-life of this compound requires four times daily... 

Monobromobenzene 1, 1,2-dibromobenzene 2, 1,3 dibromobenzene 2, 1,4-dibromobenzene 4, hexabromobenzene 5 and tetrabromobisphenol A 6 are used as plasticizers, flame retardants or intermediates for various syntheses. Except for 1, a limited number of studies regarding the toxicity and metabolism of above compounds has been performed. This report presents some studies on the hepatotoxic action (necrotic and porphyrogenic effects) of these compounds. 

In conclusion, the obtained results suggest that the studied compounds differ from the point of view of acute hepatotoxicity. Only 2 and 2 after a single dose result in equal hepatotoxicity, as found previously for monobromo-benzene. The results obtained in part of experiments in which repeated doses were used, suggest the porphyrogenic properties of the compounds. This requires, however, an extended investigation with more specific indicators of such properties. 

In summary, it can be reported that toxic cyanobacteria can produce neurotoxic, hepatotoxic, and dermatotoxic compounds that are a direct threat to animal and human water supplies. This threat increases as water bodies become more eutrophic, thus supporting higher production of toxic and nontoxic cyanobacteria. Presence of these potent natural product toxins poses an increasing threat to the maintenance of quality water supplies for agriculture, municipal, and recreational use. 

By enhancing the metabolism of trichloroethylene to its cytotoxic metabolites, compounds that induce the hepatic mixed-function oxidase system can potentiate the hepatotoxicity of trichloroethylene. 

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