Reduction in CYP1A1 and 2B2 activity at low oxygen tension

Hernández-Gutiérrez, Laura S; Camacho-Carranza, Rafael; Hernández-Ojeda, S.L.; Govezensky, Tzipe; Olguín-Reyes, S.R.; Espinosa-Aguirre, J.J.

doi:10.1016/j.toxlet.2020.05.006

Cited by 2 publications

(2 citation statements)

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Section: Resultsmentioning

confidence: 99%

“…What is important to note is that the catalytic cycle of cytochrome CYP enzymes involves the reduction of ferric hem to the ferrous state, a process that is mediated by molecular oxygen. [42] Because the concentration of molecular oxygen impacts the activities of CYP enzymes in vivo, we investigated how oxygen availability influences the activities of CYP2C9 and CYP3A following drug exposure (Figure 4). We initiated treatments 3 days after starting the cultures and maintained them for 8 days, which was sufficient to upregulate moderate to strong drug-metabolizing enzyme inducers.…”

Section: Drug Treatment Effects On Enzymatic Activities Of Hepatic Sp...mentioning

confidence: 99%

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Comparison of Engineered Liver 3D Models and the Role of Oxygenation for Patient‐Derived Tumor Cells and Immortalized Cell Lines Cocultured with Tumor Stroma in the Detection of Hepatotoxins

Mansouri,

Lamichhane,

Das

et al. 2023

Advanced Biology

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In metabolically active tumors, responses of cells to drugs are heavily influenced by oxygen availability via the surrounding vasculature alongside the extracellular matrix signaling. The objective of this study is to investigate hepatotoxicity by replicating critical features of hepatocellular carcinoma (HCC). This includes replicating 3D structures, metabolic activities, and tumor‐specific markers. The internal environment of spheroids comprised of cancerous human patient‐derived hepatocytes using microparticles is modulated to enhance the oxygenation state and recreate cell‐extracellular matrix interactions. Furthermore, the role of hepatic stellate cells in maintaining hepatocyte survival and function is explored and hepatocytes from two cellular sources (immortalized and patient‐derived) to create four formulations with and without microparticles are utilized. To investigate drug‐induced changes in metabolism and apoptosis in liver cells, coculture spheroids with and without microparticles are exposed to three hepatotoxic drugs. The use of microparticles increases levels of apoptotic markers in both liver models under drug treatments. This coincides with reduced levels of anti‐apoptotic proteins and increased levels of pro‐apoptotic proteins. Moreover, cells from different origins undergo apoptosis through distinct apoptotic pathways in response to identical drugs. This 3D microphysiological system offers a viable tool for liver cancer research to investigate mechanisms of apoptosis under different microenvironmental conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Drug Treatment Effects On Enzymatic Activities Of Hepatic Sp...mentioning

confidence: 99%