Impaired Hepatic Elimination of Paranitrophenol and Its Metabolites in the Rat following Chronic Ethanol Pretreatment

Chronic ethanol feeding has been shown to enhance hepatic microsomal drug oxidation in humans and in laboratory animals. However, the effects of chronic ethanol administration on drug conjugation are less conclusive. We have studied the effects of chronic ethanol feeding on (a) the conjugation and elimination of p‐nitrophenol (PNP) by the isolated perfused rat liver, (b) the formation of PNP glucuronide by hepatic microsomal PNP‐glucuronyltransferase in vitro and (c) the hepatic content of UDP‐glucuronic acid (UDPGA). PNP elimination from the isolated perfused rat liver was best described as a combination of parallel saturable and first‐order processes. Ethanol pretreatment did not influence the former but resulted in a 48% reduction in the rate of elimination by the latter. This was associated with a significant reduction in recovery of PNP‐glucuronide from bile, but no change in concentrations of PNP glucuronide or sulfate in perfusate. Michaelis constants and V_max for PNP‐glucuronyltransferase in native and solubilized microsomes and UDPGA concentrations in liver were not influenced by ethanol pretreatment. These results suggest that chronic ethanol treatment reduces PNP elimination in the intact liver primarily via a reduction in the biliary excretion of PNP glucuronide without altering glucuronidation per se.