RT Journal Article
SR Electronic
T1 Quantitative differences in phase I and II metabolism between rat precision-cut liver slices and isolated hepatocytes.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1274
OP 1279
VO 23
IS 11
A1 S Ekins
A1 G I Murray
A1 M D Burke
A1 J A Williams
A1 N C Marchant
A1 G M Hawksworth
YR 1995
UL http://dmd.aspetjournals.org/content/23/11/1274.abstract
AB Testosterone (250 microM), 7-ethoxycoumarin (25 microM), and 1-chloro-2,4-dinitrobenzene (CDNB, 50 microM) were used as substrates to compare phase I and II metabolism in rat precision-cut liver slices and rat hepatocytes. Overall clearance to metabolites was significantly greater in hepatocytes for testosterone (1.9- to 16.9-fold), 7-ethoxycoumarin (O-deethylation, 14.8-fold; glucuronidation, 3.1-fold), and CDNB (8.7-fold). The same metabolites for each of the substrates were detected in slices and hepatocytes. However, the ratio of sulfate to glucuronide conjugation was higher in slices, in line with the markedly slower rate of formation of 7-hydroxycoumarin. The slower rate of CDNB conjugation could not be explained by differences in the intracellular concentration 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-chloro-4-(3H)-quinazolinone as a fluorescent probe to investigate diffusion in slices and hepatocytes.