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. 2021 Mar 11;11:5648. doi: 10.1038/s41598-021-85048-1

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Monocyte chemoattractant protein 1 (MCP-1) mediated decrease in CYP3A4 activity in the liver of human breast cancer patients; proposed hypothesis. (A) The liver of breast cancer patients is exposed to increased circulating levels of MCP-1 during chemotherapy. Liver kupffer cells (hepatic macrophages) express the MCP-1 cell surface receptor C–C chemokine receptor type 2 (CCR2), and thus, MCP-1 can bind and induce an increase in the production of other inflammatory cytokines, such as interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α), and further increase levels of MCP-1 molecules. IL-6 and TNF-α bind their membrane receptors, interleukin 6 receptor (IL-6R) and tumour necrosis factor receptor 1 (TNFR1), on the surface of nearby hepatocytes, inducing inflammatory signalling cascades that regulate CYP3A4 transcription. (B) Schematic of one of the mechanisms by which inflammatory cytokines inhibit CYP3A4 transcription; as reported by Jover et al.⁵⁸, Intracellular signalling, following IL-6 binding, induces translation of CCAAT-enhancer-binding protein beta isoform LIP (C/EBPβ-LIP), an antagonist of CCAAT-enhancer-binding protein alpha (C/EBPα); C/EBPα is a known transcription factor that constitutively promotes CYP3A4 expression in hepatocytes⁵⁸.