Genotoxic mechanism of tamoxifen in developing endometrial cancer.
Increased risk of developing endometrial cancers has been observed in women treated with tamoxifen (TAM), a widely used drug for breast cancer therapy and chemoprevention. The carcinogenic effect may be due to genotoxic DNA damage induced by TAM. In fact, TAM-DNA adducts were detected in the endometrium of women treated with this drug. TAM is alpha-hydroxylated by cytochrome P450 3A4 followed by O-sulfonation by hydroxysteroid sulfotransferase, and reacts with guanine residues in DNA, resulting in the formation of alpha-(N2-deoxyguanosinyl)tamoxifen adducts. During this metabolic process, short-lived carbocations are produced at the ethyl moiety of TAM as reactive intermediates. TAM-DNA adducts promote primarily G -->T transversions in mammalian cells. The same mutations have been frequently detected at codon 12 of the K-ras gene in the endometrial tissue of women treated with this drug. TAM-DNA adducts, if not readily repaired, may act as initiators, leading to development of endometrial cancers. The reactivity of TAM metabolites with DNA is inhibited in toremifene, where the hydrogen atom has been replaced by a chlorine atom at the ethyl moiety. Therefore, toremifene may be a safer alternative to TAM. This article describes an overview of the mechanism of TAM-DNA adduct formation, mutagenic events of this adduct, and detection of TAM-DNA adducts in the endometrium of women treated with TAM.
Kim
Sung Yeon
SY
Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA.
Suzuki
Naomi
N
Laxmi
Y R Santosh
YR
Shibutani
Shinya
S
D000328:Adult; D000818:Animals; D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D002478:Cells, Cultured; D018736:DNA Adducts / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D004717:Endometrium / Q000166:cytology / Q000187:drug effects; D004965:Estrogen Antagonists / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D000882:Haplorhini; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*
D016588:Anticarcinogenic Agents; D018736:DNA Adducts; D004965:Estrogen Antagonists; D009153:Mutagens; D013629:Tamoxifen