INTER-SPECIES COMPARISON OF 7-HYDROXYCOUMARIN GLUCURONIDATION AND SULFATION IN LIVER S9 FRACTIONS

UDP glycosyltransferases (UGTs) and sulfotransferases (SULTs) are phase II enzymes that interact with a number of xenobiotics in humans and animals. Species differences in enzymatic characteristics have seldom been investigated. Liver S9 fractions are commonly used for studying phase II metabolism i...

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Published in:In vitro cellular & developmental biology. Animal 2006-01, Vol.42 (1), p.8-12
Main Authors: WANG, QING, YE, CINDY, JIA, RICHARD, OWEN, ALBERT J, HIDALGO, ISMAEL J, LI, JIBIN
Format: Article
Language:English
Subjects:
Animals
Cell Fractionation
Dogs
enzyme kinetics
Enzymes
glucuronidation
Glucuronosyltransferase - metabolism
Humans
Kinetics
Liver
Liver - chemistry
Liver - metabolism
Liver microsomes
Macaca fascicularis
Male
Metabolism
Monkeys
Rats
species difference
Species Specificity
Sulfation
Sulfotransferases - metabolism
Sulfur - metabolism
Umbelliferones - chemistry
Umbelliferones - metabolism
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Summary:UDP glycosyltransferases (UGTs) and sulfotransferases (SULTs) are phase II enzymes that interact with a number of xenobiotics in humans and animals. Species differences in enzymatic characteristics have seldom been investigated. Liver S9 fractions are commonly used for studying phase II metabolism in vitro. The objective of this study was to characterize the UGT and SULT activities in liver S9 fractions from various species including humans, monkeys, dogs, and rats. A single substrate, 7-hydroxycoumarin (7-HC), at several concentrations was incubated at 37° C with the S9 reaction matrices along with necessary cofactors. The rate of formation of two metabolites, 7-HC-glucuronide (7-HC-G) and 7-HC-sulfate (7-HC-S), was determined with Liquid Chromatography/Tanderm Mass Spectrometry (LC/MS/MS). Apparent Km and Vmax values were calculated for each species. For the UGTs, the apparent Km and Vmax for 7-HC-G formation varied greatly among different species, with dog UGTs having both the highest Km and Vmax values. In contrast to UGTs, the Km for 7-HC-S formation showed no significant difference among humans, monkeys, and rats (approximately 3 μM). However, the Km in dog was 8.7 μM. Species differences with respect to phase II metabolism must be carefully considered when selecting an in vitro model system to study various aspects of drug metabolism.
ISSN:1071-2690
1543-706X
1543-706X
DOI:10.1290/0509066.1