In the liver, as an important metabolic organ, a large number of complex signaling pathways occur, often simultaneously. Not only hepatocytes are involved in these signaling pathways, also Kupffer cells, the largest population of liver macrophages, are part of these pathways. In this work, structure-dependent molecular cell responses were established based on the adverse effects of bisphenol A and its derivatives in the hepatocyte-like cell line HepG2 indirectly co-cultured with the differentiated macrophage-like cell line THP-1 cells. The causal relationship between the effects of two additional methyl groups in bisphenol A and the depolarisation of the mitochondrial membrane, along with subsequently induced intrinsic apoptosis, has been shown. This adverse effect of the additional methyl groups could be detected through the increased secretion of the prognostic factor TNF α in the cell culture system. So, there is evidence that increases in TNF-α secretion mirrors a potentially increased chemical sensitivity in the indirect co-culture of the cells investigated. Based on the data of this work, this increased sensitivity is correlated with the increased expression and activity of metabolizing enzymes (e.g., cytochrome P450-dependent monooxygenase 1A1) and the accelerated β-oxidation of intracellular fatty acids, which results in the reduction of intracellular lipid droplets. All of these changes are due to the pro-inflammatory influence of the differentiated THP-1 cell line. Its secretion of soluble factors (e.g., cytokines) initiates certain signaling pathways. By looking into the correlation networks of these cytokines, an additive effect of the two cell lines used in this co-culture becomes obvious. However, when this indirect co-culture is replaced by using more primary cells, such as primary human immortalized hepatocytes (Fa2N-4) and primary human monocyte derived macrophages (MDM), cytokine-dependent cell-cell communication can be observed in the correlation network as well. The “inflammatory status” of the system can be influenced by the ratio of MDM to Fa2N-4 cells. For instance, an increase in the MDM cell number is associated with altered gene expression (based on transcriptome data of Fa2N-4 cells) related to an acute phase reaction. The cell system established in this work responds to the treatment with pharmaceuticals such as diclofenac and adalimumab, and to lipopolysaccharides, in terms of altered cytokine secretion. Parallels to the in vivo situation can be seen here. In conclusion, the present work provides evidence for an increased chemical sensitivity of HepG2 cells when growing in an indirect co-culture system along with THP-1 cells. Furthermore, it could be shown that indirect co-cultivation of Fa2N-4 cells and MDM would be advantageous in the detection of chemical-induced adversity in liver cells.