Case reports have indicated that patients taking therapeutic doses of acetaminophen chronically (3 weeks - 1 year) have developed liver injury; concurrent consumption of ethanol and/or inadequate diets may have enhanced their susceptibility. Ongoing studies in this laboratory on the hepatotoxicity of acetaminophen administered acutely have indicated that the susceptibility of laboratory animals to this drug-induced liver damage is significantly altered by conditions (diabetes, fasting) which alter intermediary metabolism of carbohydrates in their livers. We hypothesize that dietary alterations which modulate hepatic intermediary metabolism will also modulate the susceptibility of the animals to acetaminophen-induced hepatic necrosis, whether the drug is given or chronically. To test this hypothesis, rats will be placed on a liquid nutritionally-adequate diet (American Institute of Nutrition, AIN-76), the AIN-76 liquid diet deficient in one or more specific nutrients, or AIN-76 diet supplemented with ethanol. Susceptibility to acetaminophen hepatotoxicity will be tested after administration of the drug; (a) acutely, (b) chronically, (c), and chronically plus a challenge with a larger acute dose. Experimentally the liquid diets will be altered: first, by reducing the total nutrient value of the diet; by one-half and by one-quarter; secondly, by reducing levels of specific macronutrients (protein, fat or carbohydrate); thirdly, by inducing a specific deficiency of sulfur-containing amino acids; and lastly, by supplementing the diets with ethanol. The responses to such dietary alterations will be determined in terms of dose-response relationships on a) incidence of hepatotoxicity, on b) the metabolic disposition, and c) where applicable, on the kinetic parameters on individual pathways of acetaminophen metabolism. As appropriate, additional mechanism studies will be done to examine the effects of the diets on particular pathways of drug metabolism. For glucuronidation, glucuronyl transferase activity and levels of UDPGA and key enzymes and intermediates required for its synthesis will be determined. For sulfation, sulfotransferase activity and levels of PAPS will be measured. For the toxic pathway, levels of cytochrome P450 and GSh will be determined.
| Price, V F; Jollow, D J (1989) Effects of sulfur-amino acid-deficient diets on acetaminophen metabolism and hepatotoxicity in rats. Toxicol Appl Pharmacol 101:356-69 |
| Price, V F; Gale, G R (1987) Effects of caffeine on biotransformation and elimination kinetics of acetaminophen in mice. Res Commun Chem Pathol Pharmacol 57:249-60 |
