thiobenzamide and Necrosis

Differences in the nature and extent of hepatic injury were examined after administration of para-substituted thiobenzamides to rats. In accordance with previous studies, the extent of hepatotoxicity varied with the electron-donating ability of the substituent. There was also a good correlation between the extent of hepatic necrosis and the amount of substituted thiobenzamide sulfoxide found in the plasma after intraperitoneal dosing. The nature of the hepatic lesion, characterized as a combination of hepatic necrosis, ballooning degeneration, and biliary dysfunction, varied qualitatively with each thiobenzamide analog. When the hepatotoxicity of thiobenzamide was compared after either intraperitoneal or oral dosing, differences in the extent of hepatic necrosis, ballooning degeneration, transaminase elevation, and biliary dysfunction were observed. Intraperitoneal dosing with thiobenzamide gave less severe necrosis and more pronounced elevations in bile acids, while oral dosing led to more severe necrosis along with impaired biliary function. The route of administration was shown to dramatically affect the pharmacokinetics of thiobenzamide and thiobenzamide sulfoxide. Intraperitoneal administration of thiobenzamide gave high plasma and liver levels of both thiobenzamide and thiobenzamide sulfoxide, whereas oral administration gave slightly lower levels of the sulfoxide but much lower levels of thiobenzamide. The reason for greater hepatic necrosis after oral administration may be due to a greater ability to further metabolize the sulfoxide to a reactive metabolite in the absence of high levels of thiobenzamide.

Topics: Administration, Oral; Alanine Transaminase; Animals; Aspartate Aminotransferases; Bile Acids and Salts; Bilirubin; Chemical and Drug Induced Liver Injury; Female; Injections, Intraperitoneal; Liver; Liver Diseases; Male; Microsomes, Liver; Necrosis; Rats; Rats, Inbred Strains; Thioamides; Transaminases

Administration of thiobenzamide (TB) (0.18 mmol/100 g b.w.) to rats caused the appearance in serum and urine of a compound identified as thiobenzamide-S-oxide. When synthesized and given by oral administration, this compound induced the early appearance of liver centrilobular necrosis, impairment of glucose-6-phosphatase and aminopyrine demethylase activities, and diminished cytochrome P-450 content. Liver necrosis was suppressed by the prior administration of 20-methylcholanthrene. It is concluded that TB-S-oxide is involved, possibly as a proximate precursor, in TB-induced liver damage.

Topics: Amides; Animals; Liver; Male; Necrosis; Rats; Thioamides

Topics: Age Factors; Animals; Benzamides; Cell Nucleus; Liver; Liver Cirrhosis, Biliary; Male; Necrosis; Rats; Thioamides; Thiones; Time Factors