Refine
Keywords
- skin (1) (remove)
As an interface between an individual and its environment, the skin is a major site of direct exposure to exogenous substances. Once absorbed, these substances may interact with different biomolecules within the skin. The aryl hydrocarbon receptor (AhR) signaling pathway is one mechanism whereby the skin responds to exposures, predominantly through the induction or upregulation of metabolizing enzymes. One known physiological role of the AhR in many tissues is its involvement in the control of cell cycle progression. In skin, almost nothing is known about this physiological function. Moreover, the question whether frequently used naturally occurring phenolic derivatives like eugenol and isoeugenol impact on the AhR within the skin has rarely been studied so far. Eugenol and isoeugenol are due to their odour referred to as fragrances. The ubiquitous distribution of eugenol and isoeugenol results in an almost unavoidable contact with these substances in our daily lives. Despite this fact, their molecular mechanisms of action in skin are poorly understood. There is evidence supporting the hypothesis that these substances may impact on the AhR. On the one hand, eugenol is shown to induce cytochrome P450 1A1 (CYP1A1), a well-known target gene of the AhR. On the other hand, their known anti-proliferative properties might also be mediated by the AhR, based on its physiological function. In order to proof this hypothesis, it was investigated whether eugenol and isoeugenol impact on the AhR signaling pathway in skin cells. Results revealed that eugenol as well as isoeugenol impact on the AhR signaling pathway in skin cells. Both substances caused the translocation of the AhR into the nucleus, induced the expression of the well-known AhR target genes CYP1A1 and AhR repressor (AhRR) and exhibited impact on cell cycle progression. Both substances caused an AhR-dependent cell cycle arrest in skin cells, modulated protein levels of several cell cycle regulatory proteins, inhibited DNA synthesis and thereby reduced cell numbers. The comparison of wildtype cells to AhR knockdown cells revealed an influence of the AhR on cell cycle progression in skin cells in the absence of exogenous ligands. AhR knockdown cells exhibited a slower progression through the cell cycle caused by an accumulation of cells in the G0/G1 phase of the cell cycle and a decreased DNA synthesis rate. Modulation of cell cycle regulatory proteins involved in the transition from the G0/G1 to the S phase of the cell cycle was altered in AhR knockdown cells as well. To conclude, eugenol as well as isoeugenol were able to impact on the AhR signaling pathway in skin cells. Their molecular mechanisms of action are similar to those of classical AhR ligands, although their structural characteristics strongly differ from that of these ligands. In the absence of exogenous ligands the AhR promotes cell cycle progression in many tissues and this knowledge could be expanded on skin-derived cells within the scope of this thesis.