Differences in the effects of model inducers of cytochrome P450 on the biotransformation of scoparone in rat and hamster liver.
The hamster is known to display very high rates of monooxygenase-mediated biotransformation. In comparison with other species little knowledge has been gathered with respect to the nature of its cytochrome P450 enzymes and their respective inducibility. We studied the consequences of induction of P450 enzymes in rats and Syrian golden hamsters using the regioselective oxidative O-demethylation of the coumarin derivative scoparone. This metabolic conversion indicates differential effects of P450 inducers in the rat, in which various types of inducers cause different shifts in the isoscopoletin/scopoletin metabolite ratio (I/S-ratio). Liver microsomes from hamster not treated with P450 inducers oxidized scoparone much more efficiently than liver microsomes of untreated rats. In rat liver microsomes total demethylation rates of scoparone increased upon in vivo treatment with phenobarbital or beta-naphthoflavone. Phenobarbital reduced the I/S-ratio whereas beta-naphthoflavone caused an increase in this ratio. In hamster liver microsomes both phenobarbital and beta-naphthoflavone treatments resulted in a decrease in the I/S ratio. In this species the total scoparone demethylation rate was not much affected by phenobarbital, but beta-naphthoflavone caused a huge increase in over-all scoparone biotransformation. In both species, dexamethasone, isoniazid and clofibrate were much less effective. In contrast to the rat, in the hamster the scoparone biotransformation profile cannot be used to differentiate between phenobarbital- or beta-naphthoflavone-treated animals.
Mennes
W C
WC
Research Institute of Toxicology, University of Utrecht, The Netherlands.
Luijckx
N B
NB
Wortelboer
H M
HM
Noordhoek
J
J
Blaauboer
B J
BJ
D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D002994:Clofibrate / Q000494:pharmacology; D003374:Coumarins / Q000493:pharmacokinetics*; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D006168:Guinea Pigs; D007538:Isoniazid / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D019324:beta-Naphthoflavone
D000959:Antihypertensive Agents; D001571:Benzoflavones; D003374:Coumarins; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; C018145:scoparone; D002994:Clofibrate; D007538:Isoniazid; D010634:Phenobarbital