Drug glucuronidation and hepatic lipid microsomal membrane profile in cholestatic rats followed paracetamol intoxication

The uridin-diphosphoglucuronyl-transferase (UDP-GT) is a membrane-bound enz yme responsible for glucuronidation of endogenous and exogenous compounds. This work established the UDP-GT activity and its lipid membrane microenvir onment in two experimental models: acute paracetamol intoxication, and chol estasis followed by acute paracetamol intoxication. Cholestasis was perform ed by bile duct ligation. After 7 days animals were injected with paracetam ol (BDL-APAP group). Sham-operated rats were injected at day 7 with paracet amol (APAP group). Cholestatic and sham-operated rats injected with vehicle (BDL and control groups). UDP-GT activity was measured by a kinetic method for different substrates. Microsomal membrane phospholipid composition, ch olesterol content and ultrastructure were determined. BDL-APAP group showed an increment in the UDP-GT activity except for chloramphenicol, morphine a nd paracetamol if compared to controls and to BDL group. The same increment was observed when BDL-APAP was compared to APAP except for chloramphenicol and lorazepam. Between BDL and APAP groups similar levels of activity were detected except for paracetamol. Microsomal phospholipid profile: phosphat idylcholine showed the lowest content in the BDL group, with a significant recovery in the BDL-APAP and APAP groups. Phosphatidylserine was markedly d ecreased in the APAP group compared to the rest and phosphatidylinositol wa s decreased in all the groups if compared to control values. An increment o f phosphatidylethanolamine was seen in the APAP and BDL-APAP groups if comp ared to BDL and control values. A significant increment of microsomal chole sterol content was seen in BDL. Under these conditions, a different lipid m icroenvironment is produced, resulting in an increment of the enzyme activi ty for a variety of substrates. (C) 1999 Academic Press.