This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schild, L. J. Articles by Poirier, M. C. Search for Related Content PubMed PubMed Citation Articles by Schild, L. J. Articles by Poirier, M. C.

Formation of Tamoxifen-DNA Adducts in Multiple Organs of Adult Female Cynomolgus Monkeys Dosed with Tamoxifen for 30 Days¹

Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255 [L. J. S., R. L. D., M. C. P.]; Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079 [F. A. B., M. I. C., D. R. D.]; and Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Av. Rovisco Pais, 1049-001 Lisboa, Portugal [G. G. d. C., M. M. M.]

The use of the antiestrogen tamoxifen (TAM) is associated with an increase in endometrial cancer. TAM-induced endometrial carcinogenesis may proceed through a genotoxin-mediated pathway, although the detection of endometrial TAM-DNA adducts in exposed women is still controversial. In this study, a monkey model has been used to investigate the question of TAM-DNA adduct formation in primates. Two methods have been used to determine TAM-DNA adducts: a TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), using an antiserum that has specificity for (E)--(deoxyguanosin-N²-yl)-tamoxifen (dG-TAM) and (E)--(deoxyguanosin-N²-yl)-N-desmethyltamoxifen (dG-desmethyl-TAM) and electrospray ionization tandem mass spectrometry (ES-MS/MS) coupled with on-line sample preparation and high-performance liquid chromatography (HPLC). Mature (19 year old) cynomolgus monkeys were given either vehicle control (n = 1) or TAM (n = 3) twice daily for a total dose of 2 mg of TAM/kg body weight (bw)/day for 30 days by naso-gastric intubation. Tissues were harvested, and DNA was isolated from uterus, ovary, liver, brain cortex, and kidney. By TAM-DNA CIA, values for uterine TAM-DNA adducts in two monkeys were 0.9 and 1.7 adducts/10⁸ nucleotides, whereas values for ovarian TAM-DNA adducts in the same animals were 0.4 and 0.5 adducts/10⁸ nucleotides. Liver, brain cortex, and kidney DNA samples from the three exposed monkeys had TAM-DNA levels of 2.1–4.2 adducts/10⁸ nucleotides, 0.4–5.0 adducts/10⁸ nucleotides, and 0.7–2.1 adducts/10⁸ nucleotides, respectively. By HPLC-ES-MS/MS, the levels of TAM-DNA adducts detected in all tissues were comparable with those observed by TAM-DNA CIA. Thus, values for uterine TAM-DNA adducts ranged from 0.5 to 1.4 adducts/10⁸ nucleotides, whereas values for ovarian TAM-DNA adducts, measurable in two monkeys, were 0.2 and 0.3 adducts/10⁸ nucleotides. Liver DNA contained the highest TAM-DNA adduct levels (7.0–11.1 adducts/10⁸ nucleotides), whereas brain cortex DNA contained lower adduct levels (0.6–4.8 adducts/10⁸ nucleotides) and the lowest levels were measured in the kidney (0.2–0.4 adducts/10⁸ nucleotides). This study indicates that cynomolgus monkeys are capable of metabolizing TAM to genotoxic intermediates that form TAM-DNA adducts in multiple tissues.

This article has been cited by other articles:

				K. Brown, E. M. Tompkins, D. J. Boocock, E. A. Martin, P. B. Farmer, K. W. Turteltaub, E. Ubick, D. Hemingway, E. Horner-Glister, and I. N.H. White Tamoxifen Forms DNA Adducts in Human Colon after Administration of a Single [14C]-Labeled Therapeutic Dose Cancer Res., July 15, 2007; 67(14): 6995 - 7002. [Abstract] [Full Text] [PDF]

				S. Y. Kim, N. Suzuki, Y. R. S. Laxmi, and S. Shibutani INEFFICIENT REPAIR OF TAMOXIFEN-DNA ADDUCTS IN RATS AND MICE Drug Metab. Dispos., February 1, 2006; 34(2): 311 - 317. [Abstract] [Full Text] [PDF]

				R. Singh and P. B. Farmer Liquid chromatography-electrospray ionization-mass spectrometry: the future of DNA adduct detection Carcinogenesis, February 1, 2006; 27(2): 178 - 196. [Abstract] [Full Text] [PDF]

				S. Y. Kim, Y. R. S. Laxmi, N. Suzuki, K. Ogura, T. Watabe, M. W. Duffel, and S. Shibutani FORMATION OF TAMOXIFEN-DNA ADDUCTS VIA O-SULFONATION, NOT O-ACETYLATION, OF {alpha}-HYDROXYTAMOXIFEN IN RAT AND HUMAN LIVERS Drug Metab. Dispos., November 1, 2005; 33(11): 1673 - 1678. [Abstract] [Full Text] [PDF]

				D. H. Phillips, A. Hewer, M. R. Osborne, K. J. Cole, C. Churchill, and V. M. Arlt Organ specificity of DNA adduct formation by tamoxifen and {alpha}-hydroxytamoxifen in the rat: implications for understanding the mechanism(s) of tamoxifen carcinogenicity and for human risk assessment Mutagenesis, July 1, 2005; 20(4): 297 - 303. [Abstract] [Full Text] [PDF]

				L. J. Schild, D. H. Phillips, M. R. Osborne, A. Hewer, F. A. Beland, M. I. Churchwell, K. Brown, M. Gaskell, E. Wright, and M. C. Poirier Hepatic DNA adduct dosimetry in rats fed tamoxifen: a comparison of methods Mutagenesis, March 1, 2005; 20(2): 115 - 124. [Abstract] [Full Text] [PDF]

				F. A. Beland, M. I. Churchwell, D. R. Doerge, D. R. Parkin, D. Malejka-Giganti, A. Hewer, D. H. Phillips, P. L. Carmichael, G. Gamboa da Costa, and M. M. Marques Electrospray Ionization-Tandem Mass Spectrometry and 32P-Postlabeling Analyses of Tamoxifen-DNA Adducts in Humans J Natl Cancer Inst, July 21, 2004; 96(14): 1099 - 1104. [Abstract] [Full Text] [PDF]