Effects of cytochrome P450 inducers on tamoxifen genotoxicity in female mice in vivo.
We recently reported that administration of the antiestrogen tamoxifen (TAM) gives rise to two groups of DNA adducts in female mouse liver in vivo, as measured by 32P-postlabeling, and provided evidence that 4-hydroxytamoxifen and alpha-hydroxytamoxifen are proximate carcinogenic metabolites leading to group I and group II adducts, respectively (Randerath et al., Carcinogenesis 15: 2087-2094, 1994). Because cytochrome P450 (CYP) enzymes play an important role in TAM metabolism, in this investigation we tested the hypothesis that induction of liver CYP enzymes may affect TAM metabolism profoundly, resulting in increased or decreased TAM-DNA adduct formation in vivo. To this end, we treated female ICR mice with TAM either alone or in combination with one of several classic CYP inducers, i.e. phenobarbital (PB), beta-naphthoflavone (BNF), and pregnenolone-16 alpha-carbonitrile (PCN), and determined the levels of 32P-postlabeled TAM-DNA adducts and the activities of several CYP-dependent enzymes. Each of the inducers greatly diminished levels of group II, but did not affect group I adducts. TAM elicited induction of benzphetamine N-demethylase activity in liver, while activities of other enzymes were not affected. TAM, when given in combination with BNF, elicited a synergistic induction of ethoxyresorufin O-deethylase (EROD) (CYP1A1) and methoxyresorufin O-demethylase (MROD) (CYP1A2) activities. Likewise, PCN given along with TAM caused synergistic induction of EROD and ethylmorphine N-demethylase activities. There was no synergism between PB and TAM, however. Overall, the results further support the existence of two pathways of TAM metabolism to DNA-reactive electrophiles and strongly suggest that the classic CYP inducers tested enhance detoxication of TAM to non-genotoxic metabolites.
Moorthy
B
B
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
Sriram
P
P
Randerath
E
E
Randerath
K
K
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D018736:DNA Adducts / Q000032:analysis; D004790:Enzyme Induction; D004965:Estrogen Antagonists / Q000633:toxicity*; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D010634:Phenobarbital / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D013629:Tamoxifen / Q000378:metabolism / Q000633:toxicity*
D018736:DNA Adducts; D004965:Estrogen Antagonists; D013629:Tamoxifen; D011285:Pregnenolone Carbonitrile; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital