Effect of reduced hepatic energy state on acetaminophen conjugation in rats

The effect of decreased hepatic energy state on xenobiotic conjugation was examined in vivo. The pharmacokinetics of acetaminophen, a drug that is conjugated with glucuronic acid, sulfate and glutathione, was analyzed in rats when the hepatic energy state had been decreased by ethionine or fructose. Treatment with ethionine or fructose reduced the hepatic adenosine triphosphate/diphosphate ratio by 30 to 65% and 43 to 54% and the phosphorylation potential by 50 to 80 and 43%, respectively. Ethionine treatment increased uridine triphosphate (UTP) and other UTP-derived nucleotides. However, uridine diphosphoglucuronic acid levels were decreased by 44% whereas uridine diphosphoglucose concentration was increased by 20%. This effect may be due to a decrease in redox state. Fructose treatment reduced the concentrations of UTP and UTP-derived nucleotides. Uridine diphosphoglucose was reduced by 50% and uridine diphosphoglucuronic acid by about 40%. Ethionine and fructose also decreased glutathione and adenosine 3'-phosphate 5'-phosphosulfate concentrations in the liver by 30 to 50%. During the period of decreased energy state, biliary and urinary excretion of acetaminophen (2 mmol/kg i.v.) and its metabolites was reduced 57% by ethionine and 66% by fructose. This was caused by decreased synthesis and excretion of the conjugates. Synthesis of the conjugates was impaired because of decreased hepatic cosubstrate levels. The present data suggest that energy state must be severely compromised before decreases in conjugation are observed in vivo. Thus, it is unlikely that energy state is often a limitation in the conjugation and excretion of xenobiotics.