Comparison of the DNA adducts formed by tamoxifen and 4-hydroxytamoxifen in vivo

Abstract

Tamoxifen is a liver carcinogen in rats and has been associated with an increased risk of endometrial cancer in women. Recent reports of DNA adducts in leukocyte and endometrial samples from women treated with tamoxifen suggest that it may be genotoxic to humans. One of the proposed pathways for the metabolic activation of tamoxifen involves oxidation to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. In the present study, we compared the extent of DNA adduct formation in female Sprague-Dawley rats treated by gavage with seven daily doses of 54 µmol/kg tamoxifen or 4-hydroxytamoxifen and killed 24 h after the last dose. Liver weights and microsomal rates of ethoxyresorufin O-deethylation, 4-dimethylaminopyrine N-demethylation and p-nitrophenol oxidation were not altered by tamoxifen or 4-hydroxytamoxifen treatment. Uterine weights were decreased significantly and uterine peroxidase activity was decreased marginally in treated as compared with control rats. DNA adducts were assayed by 32 P-post-labeling in combination with HPLC. Two major DNA adducts were detected in liver DNA from rats administered tamoxifen. These adducts had retention times comparable with those obtained from in vitro reactions of α-acetoxytamoxifen and 4-hydroxytamoxifen quinone methide with DNA. Hepatic DNA adduct levels in rats administered 4-hydroxytamoxifen did not differ from those observed in control rats. Likewise, adduct levels in uterus DNA from rats treated with tamoxifen or 4-hydroxytamoxifen were not different from those detected in control rats. These data suggest that a metabolic pathway involving 4-hydroxytamoxifen is not a major pathway in the activation of tamoxifen to a DNA-binding derivative in SpragueDawley rats.

Extensive Chromosomal Breaks Are Induced by Tamoxifen and Estrogen in DNA Repair-Deficient Cells

“…The main adducts detected in rats and humans treated with TAM are thus formed by ␣-OHTAM, whereas 4-OHTAM also efficiently forms DNA adducts by oxidation (4,18). Likewise, 4-OHE 2 , which forms DNA adducts more efficiently than does E 2 or 2-OHE 2 (2), induced chromosomal breaks in a dose-dependent manner in the present study.…”

Tamoxifen Induction of Aryl Sulfotransferase and Hydroxysteroid Sulfotransferase in Male and Female Rat Liver and Intestine

“…In general, the toxicity of tamoxifen is determined by the formation rate of ␣-hydroxy tamoxifen (␣-OH TAM) and 4-hydroxy tamoxifen (4-OH TAM), which is catalyzed by the phase I enzyme cytochrome P450 (Boocock et al, 2000;Kasahara et al, 2002). ␣-OH TAM formation has been reported to initiate bioactivation (Beland et al, 1999;Boocock et al, 2000), whereas 4-OH TAM formation leads to the detoxification pathway (Crewe et al, 1997;Dehal and Kupfer 1997;Chen et al, 2002). N-Demethylation by CYP3A (Jacolot et al, 1991) and N-oxidation of TAM by flavin monooxygenase (Mani et al, 1993) has also been regarded as a detoxification pathway.…”

Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen

“…27,28 Another hypothesis stipulates a possible genotoxic effect of tamoxifen with formation of DNA adducts, but is still controversial. [29][30][31][32][33] The aim of our study was to analyze the expression of selected molecular markers in patients who developed endometrial carcinoma following tamoxifen exposure.…”