http://hdl.handle.net/10029/4902 Wed, 19 Jun 2013 13:13:02 GMT 2013-06-19T13:13:02Z http://hdl.handle.net/10029/11381 Title: Structure elucidation of sildenafil analogues in herbal products. Authors: Blok-Tip, L; Zomer, B; Bakker, F; Hartog, K D; Hamzink, M; Hove, J ten; Vredenbregt, M; Kaste, D de Abstract: The structure of unknown compounds present in herbal products was elucidated using liquid chromatography-electrospray ionization-mass spectrometry, direct-infusion electrospray ionization-mass spectrometry, and nuclear magnetic resonance. Compounds 1-3 were identified as sildenafil analogues, 1 bearing an N-ethylpiperazine moiety instead of an N-methylpiperazine, and an acetyl group instead of the sulfonyl group, named acetildenafil, 2 bearing an N-ethylpiperazine moiety instead of an N-methylpiperazine (homosildenafil), and 3 bearing an N-hydroxylethylpiperazine moiety instead of an N-methylpiperazine, named hydroxyhomosildenafil. When analysing products marketed for penile erectile dysfunction or marketed as aphrodisiacs, attention should be given to the possible presence of these components. Sun, 01 Aug 2004 00:00:00 GMT http://hdl.handle.net/10029/11381 2004-08-01T00:00:00Z http://hdl.handle.net/10029/8397 Title: Tissue specific mutagenic and carcinogenic responses in NER defective mouse models. Authors: Wijnhoven, Susan W P; Hoogervorst, Esther M; Waard, Harm de; Horst, Gijsbertus T J van der; Steeg, Harry van Abstract: Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) are - except for the skin - not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features. Wed, 03 Jan 2007 00:00:00 GMT http://hdl.handle.net/10029/8397 2007-01-03T00:00:00Z http://hdl.handle.net/10029/8385 Title: Toxicity of tetrabromobisphenol A (TBBPA) in zebrafish (Danio rerio) in a partial life-cycle test. Authors: Kuiper, R V; Brandhof, E J van den; Leonards, P E G; Ven, L T M van der; Wester, P W; Vos, J G Abstract: Toxicological effects of the widely used flame retardant, tetrabromobisphenol A (TBBPA) were assessed in a partial life-cycle test with zebrafish (Danio rerio). Exposure of adult fish during 30 days to water-borne TBBPA in nominal concentrations ranging from 0 (control) to 1.5 muM was followed by exposure of the offspring in early life stages up to 47 days posthatching (dph) to the same concentrations. Adults exposed to 3 and 6 muM showed severe disorientation and lethargy shortly after beginning of exposure and were euthanized. Because semistatic exposure resulted in fluctuating water concentrations, pooled fish samples were chemically analyzed for internal dose assessment. Egg production was decreased in fish exposed to TBBPA concentrations of 0.047 muM and higher, and a critical effect level of 7.2 mug/g lipid with a lower 5% confidence limit of 3.9 mug/g lipid for 50% decreased egg production was calculated. Histology of adult ovaries indicated a relative increase of premature oocytes in two surviving females exposed to 1.5 muM. Hatching of TBBPA-exposed larvae was decreased except in animals exposed to 0.375 muM. In the highest exposure concentration, early posthatching mortality was high (81%) in larvae and the surviving juveniles showed a significant predominance of the female phenotype. Exposure of eggs from control parents up to 6 muM TBBPA resulted in increasing malformation and pericardial fluid accumulation from 1.5 muM; at higher concentrations, all embryos failed to hatch. The presented results indicate decreased reproductive success in zebrafish at environmentally relevant TBBPA concentrations. Thu, 01 Jun 2006 00:00:00 GMT http://hdl.handle.net/10029/8385 2006-06-01T00:00:00Z http://hdl.handle.net/10029/7610 Title: Application of physiologically based pharmacokinetic modeling in setting acute exposure guideline levels for methylene chloride. Authors: Bos, Peter Martinus Jozef; Zeilmaker, Marco Jacob; Eijkeren, Jan Cornelis Henri van Abstract: Acute exposure guideline levels (AEGLs) are derived to protect the human population from adverse health effects in case of single exposure due to an accidental release of chemicals into the atmosphere. AEGLs are set at three different levels of increasing toxicity for exposure durations ranging from 10 min to 8 h. In the AEGL setting for methylene chloride, specific additional topics had to be addressed. This included a change of relevant toxicity endpoint within the 10-min to 8-h exposure time range from central nervous system depression caused by the parent compound to formation of carboxyhemoglobin (COHb) via biotransformation to carbon monoxide. Additionally, the biotransformation of methylene chloride includes both a saturable step as well as genetic polymorphism of the glutathione transferase involved. Physiologically based pharmacokinetic modeling was considered to be the appropriate tool to address all these topics in an adequate way. Two available PBPK models were combined and extended with additional algorithms for the estimation of the maximum COHb levels. The model was validated and verified with data obtained from volunteer studies. It was concluded that all the mentioned topics could be adequately accounted for by the PBPK model. The AEGL values as calculated with the model were substantiated by experimental data with volunteers and are concluded to be practically applicable. Thu, 01 Jun 2006 00:00:00 GMT http://hdl.handle.net/10029/7610 2006-06-01T00:00:00Z