Genistein metabolism in liver microsomes of Wistar and mutant TR(-)-rats.
In mutant TR(-)-rats lack of the canalicular multispecific organic anion transporter prevents the biliary excretion of various phase II conjugates. In order to investigate whether this rat strain expresses high amounts of phase-I metabolic enzymes to compensate for the deficiency an in vitro study using liver microsomes of control and TR(-)-rats was conducted. While liver microsomes of non-mutant Wistar rats (control) have a higher total cytochrome P450 content, no difference is found for NADPH-reductase. Expression of cytochrome P450 (CYP) isoforms CYP1A2, 2D, and 2E1 is equal in both rat strains. CYP2B1/2 and 3A1/2, however, are significantly impaired in livers of TR(-)-rats. The CYP dependent metabolism of genistein (GEN), a widely used inhibitor of the tyrosinekinase, was studied in TR(-)- and control rat liver microsomes. Three metabolites (M1-M3) were quantified by HPLC, revealing a lower amount of M2 and M3 in TR(-)-rats. Phenobarbital-pretreatment increased the formation of M1-M3 in both rat strains (2-4 fold). Dexamethasone, a specific inducer of CYP 3A1/A2 in male rats caused an even higher induction of M1-M3 (up to 20 fold) particularly in TR(-)-rats indicating the involvement of CYP3A isozymes in genistein metabolism. Phase I-metabolism may compensate for the lack of genistein-glucuronide elimination in TR(-)-rats.
Jäger
W
W
Institute of Pharmaceutical Chemistry, University of Vienna, Austria. wjaeger@speedy.pch.univie.ac.at
Sartori
M
M
Herzog
W
W
Thalhammer
T
T
D000818:Animals; D027321:Anion Transport Proteins; D000970:Antineoplastic Agents / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D019833:Genistein / Q000378:metabolism*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009154:Mutation; D009249:NADP / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet
D027321:Anion Transport Proteins; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D007527:Isoenzymes; D009249:NADP; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D019833:Genistein; D010634:Phenobarbital