Vergleichende In-Vivo- und In-Vitro-Untersuchungen zur Bestimmung der CYP1A1-Aktivitätsveränderung  durch hormonell aktive Stoffe

Veelken, Karen

dc.contributor.advisor	Jarry, Hubertus Prof. Dr.
dc.contributor.author	Veelken, Karen
dc.date.accessioned	2015-05-15T08:43:53Z
dc.date.available	2015-06-12T22:50:05Z
dc.date.issued	2015-05-15
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0022-5FE1-D
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-5051
dc.language.iso	deu	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subject.ddc	610	de
dc.title	Vergleichende In-Vivo- und In-Vitro-Untersuchungen zur Bestimmung der CYP1A1-Aktivitätsveränderung durch hormonell aktive Stoffe	de
dc.type	doctoralThesis	de
dc.title.translated	Comparative in vivo and in vitro studies to determine the CYP1A1 activity modulation through hormonal active substances	de
dc.contributor.referee	Jarry, Hubertus Prof. Dr.
dc.date.examination	2015-06-02
dc.description.abstracteng	In numerous studies adressing the impacts of environmental chemicals and particularly endocrine disruptors on human health different mechanisms of interaction between the ERα- and AhR-signal transduction pathway as so-called "AhR-ERα crosstalk" have been discussed. Studies of possible effects of estrogen on the AhR-signal transduction pathway have been conducted rarely compared to research on the impact of ED on the ER-signal transduction pathway. Previous studies indicate an inhibitory effect of estradiol on dioxin induced CYP1A1-activity and thereby suggest a direct effect on the AhR-signal transduction pathway. Within the widely used EROD-assay estradiol as well as the xenoestrogen 4MBC showed a significant and distinct inhibition of 3MC-induced CYP1A1-activity in a H4IIE-cell culture. This effect could also be shown for estrogen-like substances and could not be inhibited by the estrogen receptor antagonist ICI. Contrary to these observations the gene expression of CYP1A1 was not influenced within the same experimental setting. In an animal test with male wildtype mice oral application of estradiol and 4MBC over three days had no significant effect on 3MC-inducted CYP1A1-gene expression. In cell homogenat of H4IIE-cell culture whose CYP1A1 was inducted by 3MC, the observed inhibitory effects within the EROD-assay on CYP1A1-activity were highly significant and dose-dependent. Beside estradiol, 4MBC and 3MC inhibitory effects could also be shown for estron, 17α-estradiol, genistein and raloxifen. In conclusion the reduced EROD-activity by estradiol and 4MBC within the cell culture was shown to be a result of a competitive inhibition of CYP1A1-enzyme. Hereby this is a serious interference factor within the usage of the EROD-assay. In addition the applied CYP1A1-inductor 3MC also functioned as a competitive substrate for CYP1A1 in higher doses. The equalization of alterations of EROD-activity and CYP1A1-gene expression widely postulated in literature has to be questioned. Competitive inhibition of the CYP1A1-enzyme within the EROD-assay should therefore be considered a contributory cause of contradicting study results. Furthermore the ignorance of these interface factors within using the EROD-assay can lead to serious underestimation of the hazard of environmental chemicals.	de
dc.contributor.coReferee	Tzvetkov, Mladen Dr.
dc.contributor.thirdReferee	Oppermann, Martin Prof. Dr.
dc.subject.ger	AhR-ERα crosstalk	de
dc.subject.ger	EROD-Assay	de
dc.subject.ger	Endokrine Disruptoren	de
dc.subject.ger	4MBC	de
dc.subject.ger	Estradiol	de
dc.subject.ger	AhR	de
dc.subject.eng	AhR-ERα crosstalk	de
dc.subject.eng	EROD-assay	de
dc.subject.eng	endocrine disruptors	de
dc.subject.eng	4MBC	de
dc.subject.eng	estradiol	de
dc.subject.eng	AhR	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5FE1-D-6
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	Medizin (PPN619874732)	de
dc.description.embargoed	2015-06-12
dc.identifier.ppn	825510163

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