EFFECT OF GENETIC OBESITY AND PHENOBARBITAL TREATMENT ON THE HEPATIC CONJUGATION PATHWAYS

The effect of genetic obesity and phenobarbital treatment on hepatic c onjugation pathways was evaluated in the obese Zucker rat. Acetaminoph en pharmacokinetic parameters were examined in vivo after a 30-mg/kg a cetaminophen intravenous bolus dose in the presence and absence of phe nobarbital treatment. Glucuronidation and glutathione conjugation path ways were studied in vitro in obese and lean Zucker rats after phenoba rbital treatment. Obese Zucker rats demonstrated a higher glucuronidat ion capacity as evidenced by a higher formation clearance of acetamino phen glucuronide and greater UDP-glucuronosyltransferase (UDPGT) activ ity toward acetaminophen and p-nitrophenol compared with lean controls . Sulfate and glutathione conjugation pathways were not affected by ge netic obesity. Obese Zucker rats possessed a higher total hepatic glut athione content due to greater liver weight. Phenobarbital treatment e nhanced glucuronidation of acetaminophen and structurally related comp ounds (i.e., p-nitrophenol) similarly in both phenotypes, but the trea tment failed to induce morphine UDPGT in the obese Zucker rat. No effe ct of phenobarbital was observed on sulfate conjugation, gamma-glutamy l cysteine synthetase activity or hepatic glutathione content in obese or lean Zucker rats. Similar increases in glutathione transferase act ivities were observed in animals of both phenotypes after phenobarbita l treatment. This study demonstrates that glucuronidation is enhanced in genetically obese rats, whereas phenobarbital causes normal inducti on of several enzymes of the glucuronidation and glutathione conjugati on pathways in the obese Zucker rat. However, morphine UDPGT was not i nduced by phenobarbital, suggesting that obese Zucker rats may possess a defect in the induction of this enzyme similar to that already desc ribed for the CYP2B gene in this strain.