Assessment of rat liver slices as a suitable model system for studying the simultaneous sulphation and glucuronidation of phenolic xenobiotics.
1. In most mammals, the xenobiotic 1-naphthol undergoes conjugation to produce predominantly the sulphate and glucuronide metabolites. 2. Using 1-naphthol, we established and validated rat liver slices as a model system to assess simultaneously the relative contributions of sulphation and glucuronidation to the metabolism of simple phenolic xenobiotics. 3. Determination of kinetic parameters for 1-naphthol sulphation showed identical affinity (Km approximately 5 microM) in rat liver slices and in rat liver cytosol. 4. In liver slices, at low substrate concentrations (10 microM 1-naphthol), sulphation was the predominant pathway but was readily saturated, whereas at high concentrations of 1-naphthol (100 microM) glucuronidation predominated. 5. In subcellular fractions, the Km for sulphation of 1-naphthol (5 microM) by liver cytosol was substantially lower than the Km for glucuronidation of 1-naphthol (48 microM) in liver microsomes, indicating saturation of sulphation by acceptor substrate was principally responsible for the shift towards glucuronidation at higher concentrations of 1-naphthol.
Oddy
E A
EA
Department of Molecular & Cellular Pathology, University of Dundee, Ninewells Hospital and Medical School, UK.
Manchee
G R
GR
Coughtrie
M W
MW
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009284:Naphthols / Q000378:metabolism; D010636:Phenols / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013431:Sulfates / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism* / Q000493:pharmacokinetics
D005965:Glucuronates; D009284:Naphthols; D010636:Phenols; D013431:Sulfates; D015262:Xenobiotics; C029350:1-naphthol