Induction of CYP2B1 and 3A1, and associated monoxygenase activities by tamoxifen and certain analogues in the livers of female rats and mice.
Previous studies suggest long-term feeding of tamoxifen (Z-1-[4-(2-dimethylamino-ethoxy)phenyl]1,2-diphenyl-1-butane) to rats gives rise to liver tumours, while mice are resistant. The effects of tamoxifen on cytochrome P450 isoenzymes and associated monoxygenase activities in the livers of female Fischer rats and C57Bl/6 and DBA/2 mice have been compared. Total microsomal cytochrome P450 was not induced in the livers of rats given tamoxifen (45 mg/kg daily for 4 days) and was in fact significantly reduced after 3 days treatment. In contrast, there was a 30-60-fold increase in the metabolism of benzyloxy- and pentoxyresorufins to resorufin. Ethoxyresorufin O-deethylase was induced only 2.5-fold. The regio- and stereo-specific hydroxylation of testosterone following tamoxifen pretreatment of rats showed a general time- and dose-dependent induction. 6 beta- and 16 alpha-hydroxylation of testosterone together with oxidation to androstenedione were increased 2-3-fold while 2 beta-hydroxylation was induced only marginally, suggesting that tamoxifen produces a mixed pattern of induction with a significant phenobarbitone-like component. No induction of the 2 beta- or 6 beta-hydroxylation pathway occurred in either mouse strain. In rats, immunoblotting experiments with polyclonal antibodies raised against CYP2B1 or 3A1 showed that tamoxifen pretreatment resulted in 2-3-fold increases in both CYP2B1, 2B2 and 3A1 proteins, relative to controls. Immunohistochemistry of rat liver sections showed a centrilobular localization of these induced proteins. Similar patterns of induction as measured by immunoblotting experiments and testosterone hydroxylation were seen following the administration of structurally related analogues, toremifene and droloxifene (3-hydroxytamoxifen), thought to be non-carcinogenic in the rat. No induction of these monooxygenase activities was seen in C57Bl/6 mice and only small increases in benzyloxy and pentoxyresorufin metabolism were in DBA/2 mice. It is suggested that the induction of cytochrome P450-dependent activities by tamoxifen may result in accelerated liver metabolism of this drug with important implications for the disposition of tamoxifen in vivo and also for its metabolic conversion to genotoxic metabolite(s). The difference in inducibility of cytochrome P450-dependent monooxygenase activities between rats and mice offers a plausible and testable hypothesis that the difference in tamoxifen metabolism between the two species may contribute to their carcinogenic response to tamoxifen.
White
I N
IN
MRC Toxicology Unit, Carshalton, Surrey, U.K.
Davies
A
A
Smith
L L
LL
Dawson
S
S
De Matteis
F
F
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D015786:Cytochromes b5 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010105:Oxygenases / Q000096:biosynthesis*; D051381:Rats; D011916:Rats, Inbred F344; D039181:Steroid 16-alpha-Hydroxylase; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000633:toxicity; D013739:Testosterone / Q000378:metabolism
D007527:Isoenzymes; D013629:Tamoxifen; D013739:Testosterone; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase