Effect of N,N-didesmethyltamoxifen upon DNA adduct formation by tamoxifen and alpha-hydroxytamoxifen.
Tamoxifen undergoes sequential metabolism to N-desmethyltamoxifen and N,N-didesmethyltamoxifen. Whereas N-desmethyltamoxifen is a major metabolite in humans, nonhuman primates, and rats, appreciable concentrations of N,N-didesmethyltamoxifen are formed in humans and nonhuman primates but not in rats. This difference in the extent of N,N-didesmethyltamoxifen formation may be important because it has been proposed that N,N-didesmethyltamoxifen inhibits the cytochrome P450 (CYP)-catalyzed alpha-hydroxylation of tamoxifen and resultant tamoxifen-DNA adduct formation. To test this hypothesis directly, we compared the extent of tamoxifen-DNA adduct formation in rats co-administered 27micromol N,N-didesmethyltamoxifen per kg body weight and either 27micromol tamoxifen per kg body weight or 27micromol alpha-hydroxytamoxifen per kg body weight daily for 7days. Female Sprague-Dawley rats treated with N,N-didesmethyltamoxifen had a 44% decrease (p >0.05) in CYP 3A2 content (the CYP isoform responsible for tamoxifen alpha-hydroxylation), an 18% decrease (p =0.010) in CYP 3A activity, and higher blood levels of tamoxifen and N-desmethyltamoxifen compared to rats treated with solvent. Total tamoxifen-DNA adduct levels were 4.1-fold higher (p <0.001) in rats given alpha-hydroxytamoxifen as compared to tamoxifen. N,N-Didesmethyltamoxifen treatment caused a 1.2-fold increase in total tamoxifen-DNA adduct levels with both tamoxifen and alpha-hydroxytamoxifen, a difference that was not significant. These results indicate that, with this experimental model, N,N-didesmethyltamoxifen does not impair the metabolism of tamoxifen to a reactive electrophile.
Gamboa da Costa
Gonçalo
G
Centro de Química Estrutural, Instituto Superior Técnico, Universidade Técnica de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
Marques
M Matilde
MM
Fu
Xin
X
Churchwell
Mona I
MI
Wang
Yu-Ping
YP
Doerge
Daniel R
DR
Beland
Frederick A
FA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D018736:DNA Adducts / Q000032:analysis / Q000737:chemistry / Q000187:drug effects*; D005260:Female; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000633:toxicity*
D018736:DNA Adducts; D008565:Membrane Proteins; C122072:N,N-didesmethyltamoxifen; C110902:alpha-hydroxytamoxifen; D013629:Tamoxifen; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A