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TY  - THES
AU  - Randerath, Isabella Eva
TI  - Untersuchung zur metabolischen Aktivierung und Toxizität niedrigchlorierter, polychlorierter Biphenyle in transgenen Zelllinien
PB  - RWTH Aachen University
VL  - Dissertation
CY  - Aachen
M1  - RWTH-2024-09639
SP  - 1 Online-Ressource : Illustrationen
PY  - 2024
N1  - Veröffentlicht auf dem Publikationsserver der RWTH Aachen University
N1  - Dissertation, RWTH Aachen University, 2024
AB  - In this work, the metabolism of four polychlorinated biphenyls (PCBs, see picture 1.1) was studied in vivo and in vitro. First, Drosophila melanogaster was confirmed as a model system for the metabolism of PCBs. Significant effects on the survival of Drosophila melanogaster exposed to a concentration of 100 µM PCB 28 were found in vivo. The other three PCBs (PCB 52, PCB 101 and PCB 118) showed no effect on mortality. In addition, a screening procedure with Drosophila melanogaster revealed four enzymes that are presumably responsible for the metabolism of the four PCBs. These are the enzymes Cyp18a1, Cyp307a2, Cyp9b1 and Cyp9f2. In the procedure, it was also possible to determine the metabolites that are derived from the four PCBs during physiological processes in the body. In the case of PCB 52, one more metabolite was identified in Drosophila than in human plasma. Therefore, other human samples were also examined and both metabolites of PCB 52 were found in human urine. The human orthologues of the enzymes found are CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. In order to be able to investigate the metabolism in more detail, stable cell lines were generated that overexpress the enzymes. For PCB 28, PCB 52 and PCB 101, CYP2A6 could be identified as the main enzyme of human metabolism. During the study of respiratory activity, PCB 28 was shown to have cytotoxic effects and PCB 52 and PCB 101 cytostatic effects. In addition, PCB 28 and PCB 101 showed genotoxic effects in the generation of double-strand breaks and increased mutagenicity through an increase in micronuclei during cell division. As a further pathway of metabolism, the possibility of the trichlorinated PCB 28 being dechlorinated by CYP enzymes was investigated. The results show that a dichlorinated metabolite is formed, which by HPLC-MS/MS analysis is 3-OH-PCB15. The results were generated in vitro in bactosomes and in cells overexpressing CYP1A2, confirming the observations and conjectures from human samples. In the course of this work, in vivo effects on lethality in Drosophila melanogaster and in vitro cytotoxic and genotoxic and mutagenic effects were shown for PCB 28. In vivo cytostatic effects were shown for PCB 52 and PCB 101, and genotoxic as well as mutagenic effects were also shown for PCB 101. In this work, no effects were found for the dioxin-like PCB 118, since only minimal metabolism could be achieved.
LB  - PUB:(DE-HGF)11 ; PUB:(DE-HGF)3
DO  - DOI:10.18154/RWTH-2024-09639
UR  - https://publications.rwth-aachen.de/record/994984
ER  -