A requirement of hepatocytes incorporated into an artificial liver support system will be preservation of in vivo metabolism of the cultured hepatocytes. The metabolic fate of a low (15 mg/kg), medium (125 mg/kg), and high (300 mg/kg) dose of acetaminophen (APAP) was determined in male and female rats. Male rats excreted more APAP as the sulfate conjugate than female rats, which correlated with the twofold greater APAP sulfotransferase activity in the male versus female rats (301 +/- 24 vs. 156 +/- 18 pmol/mg protein/min). Also, as sulfate conjugation became saturated, there was a dose-related shift in APAP metabolism to glucuronide conjugation in both genders. After sacrifice, hepatocytes were cultured with APAP (0, 150, 250, 500, and 1,000 [mu]M). Gender differences in APAP sulfation and glucuronidation persisted in culture for up to 4 days, with sulfation predominating in the male rats, similar to that seen in vivo. With increasing APAP dose, there was a saturation of sulfate conjugation and a shift to glucuronidation as observed in vivo. APAP sulfation and glucuronidation by freshly isolated cultured hepatocytes in vitro can replicate in vivo metabolism.
(C)1990 American Society of Artificial Internal Organs