Dokument: Assessment of chromosomal genotoxicity of steroidal hormones related to drug development

Titel:	Assessment of chromosomal genotoxicity of steroidal hormones related to drug development
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=6735
URN (NBN):	urn:nbn:de:hbz:061-20080117-105545-1
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Dorn, Susanne [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 1,68 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 16.01.2008 / geändert 22.01.2008
Beitragende:	Prof. Dr. Dr. Bolt, Hermann M. [Gutachter] Prof. Dr. Wunderlich, Frank [Gutachter] Prof. Dr. Greven, Hartmut [Gutachter]
Stichwörter:	genotoxicity, hydrophobic interactions, steroidal hormones, drug development
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	For the safety assessment of drugs balancing beneficial versus toxic effects is pivotal. As genotoxic compounds may pose a risk of carcinogenicity, the evaluation of genotoxicity is an integral part of the toxicological assessment of drug candidates. Positive results in standard genotoxicity tests often lead to a discontinuation of drug development. In the chromosomal aberration test (CAT), positive results are often obtained in vitro at high, sometimes cytotoxic concentrations. The toxicological relevance of such effects must be questioned. Recently, existing guidelines for genotoxicity testing are under discussion regarding the interpretation of positive in vitro genotoxicity tests. In proposed revisions, the relevance is made dependent on a “weight of evidence” (WoE) approach. This must be seen against the background of current discussions in the scientific community on the relevance of threshold effects in chromosomal genotoxicity, as a number of “indirect” mechanisms have been described that may result in positive genotoxicity results, including generation of reactive oxygen species (ROS), cytotoxicity and apoptosis. Such mechanisms are characterized by no-observed-effect-concentrations (NOECs), below which no genotoxicity is induced. Schultz and Önfelt (2000) have proposed a concept connecting the lipophilicity of chemicals with a non-specific genotoxicity on a chromosomal level. The induction of aneuploidy was related to the lipophilicity (log P) of non-specifically acting chemicals, whereas specific toxicants acted already at concentrations consistently lower than predicted based on their log P. The present thesis aimed at investigating, whether the concept of Schultz and Önfelt (2000) and its underlying principles were applicable to hormonal steroids in the course of drug development. Quantitative Structure Activity Relationship (QSAR) modelling procedures were applied, to find additional physicochemical parameters for the modelling of non-specific chromosomal genotoxicity. Also mechanistic backgrounds of chromosomal genotoxicity, such as the induction of apoptosis, cell cycle arrest, formation of ROS, and the influence of cytotoxicity were matters of the present study. The genotoxic potential of 16 androgenic or progestational steroids was assessed in Chinese hamster V79 cells, using the micronucleus (MN) assay in vitro. Thus, the original database of Schultz and Önfelt was considerably broadened. Available existing sets of MN assay data were incorporated. Applying the statistical procedure of “robust regression” it was seen that compounds with a known specific mode of action of chromosomal genotoxicity were separated as statistical outliers from the cluster of non-specific compounds, when genotoxicity was plotted against the log P. In addition, 10 other molecular descriptors were determined and equations (linear and quadratic terms) were set up relating these descriptors (up to three in combination) with effective concentrations in the MN assay. The best fitting single property to describe non-specific genotoxicity was again log P. Combinations of (a) the numbers of hydrogen bond acceptors, the polar surface and total surface areas of molecules, and (b) the dipole moment, polar surface and total surface, resulted in an optimization of correlations. Hence, the relation of polar surface to the total molecular surface appears pivotal to determine a non-specific chromosomal genotoxicity of lipophilic compounds. The genotoxicity of the steroids studied was independent of ROS and of apoptosis induction. Cell cycle arrest in G2/M phase was seen for a number of steroids as consequence of the compound’s genotoxic effect, or as a factor limiting genotoxicity, leading to a “bell-shaped” concentration-response in MN induction. The cytotoxic potencies of the steroids were generally comparable; this parameter was not correlated with positive genotoxicity. This indicates that cytotoxicity and genotoxicity were independent processes. Cytotoxicity may confound genotoxicity results, and is a usual cut-off criterion in genotoxicity tests. Regarding the toxicological relevance of positive genotoxicity results, two issues appeared to be crucial: (a) the interdependence of cytotoxicity and genotoxicity, cytotoxicity being a cut-off criterion in genotoxicity assays. Thus, in critical cases, a narrow concentration scaling is indicated. (b) Lipophilic substances generally display a non-specific genotoxicity, due to hydrophobic interactions. By using molecular descriptors, this non-specific genotoxicity is well predictable. For practical purposes, the log P value is a suitable single descriptor. Based on the results of the present thesis, a general procedure is proposed, which could be used in pharmaceutical compound development, to separate specific from non-specific modes of action of chromosomal genotoxicity.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie
Dokument erstellt am:	22.01.2008
Dateien geändert am:	22.01.2008
Promotionsantrag am:	24.10.2007
Datum der Promotion:	20.12.2007