QUANTITATIVE DIFFERENCES IN PHASE-I AND PHASE-II METABOLISM BETWEEN RAT PRECISION-CUT LIVER SLICES AND ISOLATED HEPATOCYTES

Testosterone (250 mu M), 7-ethoxycoumarin (25 mu M), and 1-chloro-2,4- dinitrobenzene (CDNB, 50 mu M) were used as substrates to compare phas e I and II metabolism in rat precision-cut liver slices and rat hepato cytes, Overall clearance to metabolites was significantly greater in h epatocytes for testosterone (1.9- to 16.9-fold), 7-ethoxycoumarin (O-d eethylation, 14.8-fold; glucuronidation, 3.1-fold), and CDNB (8,7-fold ). The same metabolites for each of the substrates were detected in sl ices and hepatocytes, However, the ratio of sulfate to glucuronide con jugation was higher in slices, in line with the markedly slower rate o f formation of 7-hydroxycoumarin. The slower rate of CDNB conjugation could not be explained by differences in the intracellular concentrati on of glutathione, These data suggest that metabolism in precision-cut slices is limited by diffusion of the substrate, This was illustrated by the use of 2-(5'-chloro-2'-phosphoryloxyphenyl)-6-4 quinazolinone as a fluorescent probe to investigate diffusion in slices and hepatocy tes.