Liver hepatic cellular components

Acetaminophen causes few adverse reactions when used as directed on the label or recommended by the primary health care provider. Adverse reactions associated with the use of acetaminophen usually occur with chronic use or when the recommended dosage is exceeded. Adverse reactions to acetaminophen include skin eruptions, urticaria (hives), hemolytic anemia, pancytopenia (a reduction in all cellular components of the blood), hypoglycemia, jaundice (yellow discoloration of the skin), hepatotoxicily (damage to the liver), and hepatic failure (seen in chronic alcoholics taking the drug). 

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). 

As mentioned previously, the biotransformation of lipophilic xenobiotics by Phase I and Phase II reactions might be expected to produce a stable, water-soluble, and readily excretable compound. However, there are examples of hepatic biotransformation mechanisms by which xenobiotics are converted to reactive electrophilic species. Unless detoxified, these reactive electrophiles may interact with a nucleophilic site in a vital cell constituent, leading to cellular damage. There is evidence that many of these reactive substances bind covalently to various macromolecular constituents of liver cells. For example, carbon tetrachloride, known to be hepatotoxic, covalently binds to lipid components of the liver endoplasmic reticulum (Reynolds and Moslen 1980). Some of the reactive electrophiles are carcinogenic as well. 

---