Thioacetamide, carcinogenicity

Toxicology. Thioacetamide can cause liver and pulmonary damage it is carcinogenic to experimental animals. 

The lARC has determined that there is sufficient evidence for the carcinogenicity of thioacetamide to animals no data were available in humans. ... 

Mirkova, E.T. (1996) Activities of the rodent carcinogens thioacetamide and acetamide in the mouse bone marrow mieronueleus assay. Mutat. Res., 352, 23-30... 

As with many enzymes the role of AMP aminohydrolase in the hierarchy of metabolic catalysts is not clearly understood. Enzymic activity in muscle is markedly reduced in the dystrophic mouse (161, 162), in humans suffering from Duchanne type muscular dystrophy (163), in hypokaliemic periodic paralysis (164), and upon denervation of normal and dystrophic mouse gastronemii (165). Activity is reported to increase in both transplanted and primary hepatomas (151) and in precancerous livers prior to the onset of neoplasia induced by feeding or by intraabdominal injections of the potent carcinogen 3 -methyl-4-dimethyl-aminoazobenzene (166). The weak carcinogen, 4 -methyl-4-dimethyl-aminoazobenzene was not effective (166). Increases in enzyme activity concomitant with altered nuclear-nucleolar morphology, nuclear RNA content, and nuclear RNA biosynthesis were also observed after injections of thioacetamide, a hepatocarcinogen (167, 168). 

Thioacetamide acts as an indirect hepatotoxin and causes parenchymal cell necrosis. It can be metabolized in vivo to acetamide, which itself is carcinogenic. Acetamide is then hydrolyzed to acetate. Thioacetamide-induced liver necrosis has been explained by a scheme that includes the metabolic conversion of thioacetamide to its S-oxide, followed by the further metabolism of thioacetamide S-oxide to a reactive intermediate that can either bind to liver macromolecules or be further degraded to acetamide and polar products. Examples of thioacetamide s... 

There is sufficient evidence of carcinogenicity in animals. Repeated dietary administration has produced liver cell tumors in mice and bile duct and liver tumors in rats. Cirrhosis has also been observed in both rats and mice. Thioacetamide is a developmental toxin. 

The toxicity of this compound is moderate in rats an oral lethal dose is 200 mg/kg. Oral administration of thioacetamide caused liver cancer in rats and mice. It is, however, a weak liver carcinogen. Malvaldi and... 

Malvaldi, G., M. Saviozzi, V. Longo, and P. G. Gervasi. 1988. Studies on the mechanism of the carcinogenic activity of thioacetamide on rat liver. Chem. Abstr. CA 109(13) 106273a. 

Thioacetamide is almost entirely converted in vivo by rats to acetamide, which is subsequently converted to acetate. Liver slices are 3 times more active than kidney slices in this metabolism. The ability of the liver to metabolize thioacetamide so rapidly has been related to the chemicaPs hepatocarcino-genicity. However, the ultimate carcinogen is not thought to be acetamide, since thioacetamide causes hepatomas at a small fraction of the dose that is necessary for the carcinogenicity of acetamide. In phenobarbital-pretreated rats, thioacetamide, sodium diethyldithiocarbamate, thiourea, thiouracil (430), 6-methylthiouracil (431), and 6-propylthiouracil (432) cause a loss in hepatic cytochrome P-450 or inhibit the oxidiative A -demethylation of benzphetamine. This has been related to the mixed-function-oxidase-catalyzed release and covalent binding of a reactive form of sulfur to cellular components (Figure 6). 

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