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Abstracts / Toxic
oxicophore. However, we require a more fundamentalnderstanding of the role of drug chemistry and bio-hemistry in ADRs. This requires knowledge of the ulti-ate toxin, signalling in cell defence and the sequence ofolecular events, which ultimately lead to cell and tissue
amage (Park et al., 2005). In order to define the rela-ionship between chemical structure, drug metabolismnd cellular response, both in terms of cell defence andell destruction, we have developed integrated chemico-iological in vitro and in vivo models.
eferences
ark, B.K., Kitteringham, N.R., et al., 2005. Annu. Rev. Pharmacol.Toxicol. 45, 177–202.
illiams, D.P., Park, B.K., 2003. Drug Discov. Today 8 (22),1044–1050.
oi:10.1016/j.tox.2006.05.041
s tamoxifen a genotoxic carcinogen in women?
aren Brown
Cancer Biomarkers and Prevention Group, Departmentf Cancer Studies and Molecular Medicine, The Biocen-re, University of Leicester, Leicester LE1 7RH, UK
-mail address: [email protected]
The antioestrogen tamoxifen, which is widely usedn the treatment of breast cancer and has recently beenpproved for the prevention of this disease, causes anncreased incidence of endometrial cancer. The mecha-isms responsible for tamoxifen-induced carcinogenesisn humans are not known and there is much debate overhether DNA damage might be a contributing factor.his issue has been the focus of our work.
Tamoxifen treatment produces multiple DNA adductsn rat liver as a result of activation via �-hydroxylationnd sulphate conjugation, yielding a reactive esterhat binds predominantly to the N2-position of gua-ine. Analogous activation of the phase I metabolites-desmethyltamoxifen and N,N-didesmethyltamoxifenccounts for the presence of additional adducts detectedy HPLC-32P-postlabelling (Brown et al., 1999). �-ydroxytamoxifen has been reported in the plasma ofomen receiving tamoxifen treatment and we have iden-
ified CYP3A4 as the human enzyme capable of cat-lyzing the generation of this active metabolite and
esulting DNA adduct formation (Boocock et al., 2002).sing the ultra sensitive technique of accelerator masspectrometry we have shown that tamoxifen is capablef binding, at extremely low levels, to DNA in uter-
6 (2006) 12–77 27
ine (Martin et al., 2003) and colon tissue of womenadministered a single 14C-labelled therapeutic dose. Inaddition, we have demonstrated the mutagenicity of dG-N2-tamoxifen adducts in human fibroblasts and foundthat nucleotide excision repair plays a role in the removalof these lesions (McLuckie et al., 2002, 2005). Prelimi-nary studies examining the biological effects of tamox-ifen adduct formation in an ER negative human uter-ine cell line have shown a linear relationship between�-acetoxytamoxifen dose and number of tamoxifenadducts over the range 10–150 �M. Interestingly, thepresence of ≥36 adducts/108 nucleotides correlates withthe induction of apoptosis and alterations in cell cycleprogression consistent with predicted responses to DNAdamage. Below this level, such effects are not observed.Therefore, although our studies illustrate the potentialfor tamoxifen to act as a human genotoxic carcinogenrecent results suggest that target cells may be capableof efficiently dealing with low levels of tamoxifen DNAadducts.
References
Brown, K., Heydon, R.T., Jukes, R., White, I.N.H., Martin, E.A., 1999.Carcinogenesis 20, 2011–2016.
Boocock, D.J., Brown, K., Gibbs, A.H., Sanchez, E., Turteltaub, K.W.,White, I.N.H., 2002. Carcinogenesis 23, 1897–1901.
Martin, E.A., Brown, K., Gaskell, M., Al-Azzawi, F., Garner,R.C., Boocock, D.J., Mattock, E., Pring, D.W., Dingley, K.,Turteltaub, K.W., Smith, L.L., White, I.N.H., 2003. Cancer Res.63, 8461–8465.
McLuckie, K.I.E., Routledge, M.N., Brown, K., Gaskell, M., Farmer,P.B., Roberts, G.C., Martin, E.A., 2002. Biochemistry 41,8899–8906.
McLuckie, K.I.E., Crookston, R.J., Gaskell, M., Farmer, P.B., Rout-ledge, M.N., Martin, E.A., Brown, K., 2005. Biochemistry 44,8198–8205.
doi:10.1016/j.tox.2006.05.042
Genotoxicity testing: A critical review of currentapproaches and risk assessment
James M. Parry
Centre for Molecular Genetics and Toxicology, MargamBuilding, University of Wales Swansea, Swansea SA28PP, UK
The standard (and now routine) methods used in theassessment of the genetic activity of chemicals are the
product of the enthusiasm and research efforts of a num-ber of individuals followed by the extensive efforts of alarger number involved in validation studies includingthose organised by the UKEMS. Initial assay devel-