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Justenhoven C.,Robert Bosch GmbH | Justenhoven C.,University of Tübingen | Winter S.,Robert Bosch GmbH | Winter S.,University of Tübingen | And 9 more authors.
Cancer | Year: 2010

Background: CYP3A enzymes, due to their role in the metabolism of steroid hormones, are suggested to affect carcinogenesis of hormone-related cancers. The purpose of the present study was to evaluate the association between polymorphisms located in CYP3A43, breast cancer risk, and tumor characteristics. Methods: A 3-plex matrix-assisted laser desorption ionization time of flight mass spectrometry assay has been established for CYP3A43-74-delA (CYP3A43*2A), CYP3A43-1018-C>G (CYP3A43*3), and CYP3A43-1047-C>T (CYP3A43*1B) polymorphisms, and 1021 breast cancer cases and 1015 age-matched, population-based controls from the German GENICA collection have been genotyped. Results: No differences in genotype frequencies between cases and controls were observed, indicating that CYP3A43-74-delA is not associated with breast cancer risk. Subgroup analyses showed an association between the CYP3A43-74-delA allele and high-grade tumors (odds ratio, 1.74; 95% confidence interval, 1.14-2.65 [P =.010 and Ptrend =.012]). Conclusions: The data support the notion that the CYP3A43-74-delA variant may result in decreased protein and/or activity levels, and this may further lead to increased hormone levels to promote tumor cell growth and hinder differentiation. Cancer 2010. © 2010 American Cancer Society. CYP3A43 is involved in the metabolism of steroid hormones. The authors observed an association between the CYP3A43 74 del A polymorphism and grade of breast tumors (odds ratio, 1.74; Ptrend =.012). The variant allele may lead to increased steroid hormone levels promoting growth of tumor cells and hinder differentiation. Copyright © 2010 American Cancer Society.

Koch H.M.,Institute for Prevention and Occupational Medicine of German Social Accident Insurance | Christensen K.L.Y.,U.S. Environmental Protection Agency | Harth V.,Institute for Prevention and Occupational Medicine of German Social Accident Insurance | Harth V.,Saarland University | And 2 more authors.
Archives of Toxicology | Year: 2012

An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of *60 lg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 h postdose. For both DnBP and DiBP, the majority of the dose was excreted in the first 24 h (92.2 % of DnBP, 90.3 % of DiBP), while only\1 % of the dose was excreted in urine on day 2. In each case, the simple monoesters were the major metabolites (MnBP, 84 %; MiBP, 71 %). For DnBP, *8 % was excreted as various side chain oxidized metabolites. For DiBP, approximately 20 % was excreted mainly as the oxidized side chain metabolite 2OH-MiBP, indicating that the extent of oxidative modification is around 2.5 times higher for DiBP than for DnBP. All DnBP and DiBP metabolites reached peak concentrations between 2 and 4 h post-exposure, followed by a monotonic decline. For DnBP metabolites, the elimination halftime of MnBP was 2.6 h; longer elimination halftimes were estimated for the oxidized metabolites (2.9-6.9 h). For DiBP metabolites, MiBP had the shortest halftime (3.9 h), and the oxidized metabolites had somewhat longer halftimes (4.1 and 4.2 h). Together with the simple monoesters, secondary oxidized metabolites are additional and valuable biomarkers of phthalate exposure. This study provides basic human metabolism and toxicokinetic data for two phthalates that have to be considered human reproductive toxicants and that have been shown to be omnipresent in humans. © Springer-Verlag Berlin Heidelberg 2012.

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