Ethanol prevents from acetaminophen inducible hepatic necrosis by inhibiting its metabolic activation in mice

Concomitant administration of a single acute dose of ethanol (4 g/kg) protected mice from the hepatocellular injury observed upon administration of a large dose of acetaminophen (400 mg/kg). This was evidenced by the normal histological appearances of liver sections and by the lowered serum aminotransferase activities in mice treated with ethanol and acetaminophen together. In the mice treated with acetaminophen alone, along with the hepatic necrosis, the hepatic microsomal aminopyrine N-demethylase activity was decreased. However, co-administration of ethanol prevented this acetaminophen dependent inhibition on the microsomal mixed function oxidase activity. Pharmacokinetic studies indicated that the concentration of un-metabolized drug in the blood was increased in the ethanol treated mice. Furthermore, upon co-administration of ethanol, although the biliary levels of acetaminophen metabolites (glucuronide, sulfate and cysteine conjugates) were decreased, the level of unmetabolized acetaminophen was increased. Our findings suggest that co-administration of an acute dose of ethanol reduces the degree of hepatocellular necrosis produced by a large dose of acetaminophen and this ethanol dependent protection is, in major part, afforded by suppression of the hepatic microsomal mixed function oxidase activity catalyzing the metabolic activation of acetaminophen.

Effect of Serotonin on Gastric Secretion in the Dog

Heidenhain pouch secretion in response to small dose of serotonin was studied in conscious dogs. A single subcutaneous injection of 0.5 to 2.0 mg of serotonin produced no changes in spontaneous fasting secretion; however, the milk-induced secretion was greatly inhibited by the same dose. This inhibition was abolished by treatment of dibenzyline or LSD(d-lysergic acid die- thylamide). LSD alone enhanced the response of gastric secretion to milk. Constant intravenous infusion of serotonin, at levels of 3 to 10 microgram/kg/min was associated with a significant increase in the volume of gastric juice aspirated from three anesthetized dogs, but the acidity of juice varied very slightly. However, when histamine is given as much as 0.8 to 3 microgram/kg/min, a marked increase in both the volume and acidity was observed. A significant elevation of mucin content in the juice obtained from the Heidenhain pouch was seen in dogs receiving a single subcutaneous injection of 1.0 mg of serotonin. In case of histamine, the mucin content of pouch juice was not relatively increased and merely an increase in the total amount of mucin secondary to the volume increase was seen. The observed increase in mucin by serotonin was inhibited by LSD, BOL (2-bromo-d-lysergic acid diethylamide) or dibenzyline, and mildly by morphine. Atropine or hexamethonium did not block the response of mucin production to serotonin. The gastrointestinal motility elicited by serotonin was not affected by these agents. It is felt that the receptor(s) responsible for the mucin production in the dog belongs to the D-receptor types postulated by Gaddum and Picarelli.