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Human hepatocytes – PXB-cells® – 2020. Part II

Human hepatocytes – PXB-cells® – 2020. Part II

In our previous post we summarized 2020 publications where PXB-cells® were used in lipid metabolism, drug metabolism and hepatitis B studies. Here we bring to your attention five 2020 publications which discuss the use of PXB-cells® in toxicity-related applications (in 2D and in 3D formats).

Ikeyama, Y. et al. Toxicol in Vitro. 2020; 65: 104785. https://pubmed.ncbi.nlm.nih.gov/31991145/

Mitochondria toxicity assessment with PXB-cells and Cryopreserved Human Hepatocytes. Image modified from the Graphical Abstract of the Ikeyama Y. et al. Toxicol. in Vitro 2020; 65: 104785.

“Successful energy shift from glycolysis to mitochondrial oxidative phosphorylation in freshly isolated hepatocytes from humanized mice liver”

Ikeyama et al. showed that PXB-cells® in the galactose culture had a higher level of intracellular ATP than those in the glucose culture. This result was not observed in cryopreserved human hepatocytes (CHH) lots: a total of 5 out of 6 CHH lots tested were not able to survive after sugar resource substitution with galactose. PXB-cells® showed high viability regardless the substitution of sugars. More details: https://kmthepatech.com/mitochondrial-toxicity-in-pxb-cells/

Ide, I. et al. Toxicol Mech Methods. 2020; 30(3):189-196. https://pubmed.ncbi.nlm.nih.gov/31736396/

“A novel evaluation method for determining drug-induced hepatotoxicity using 3D bio-printed human liver tissue”

Ide et al. developed the 3D bio-printed liver tissue with improved viability and enhanced gene expression of enzymes related to drug metabolism and transport. Both PHH and PXB-cells® were used for 3D tissue preparation. The following three genes were evaluated in PXB-cells® based 3D tissue: CYP1A2, OATP1B1 and CYP3A4. CYP1A2 and OATP1B1 have been reported to be difficult to maintain its long-term expression; and CYP3A4 is generally known as the most important drug metabolism related enzyme. Gene expression levels in 3D bio-printed liver tissue based on PXB-cells® were maintained for about 1 month.

Ishida, Y. et al. PLoS One. 2020; 15(9): e0239540. https://pubmed.ncbi.nlm.nih.gov/32966316/

Chemical structure of aflatoxin B1

“Detection of acute toxicity of aflatoxin B1 to human hepatocytes in vitro and in vivo using chimeric mice with humanized livers”

Ishida et al. paper highlights that the quality of PXB-cells® allows the study of long-term exposure (6 or 14 days) at a low dose and shows time-dependent cytotoxicity of relatively low levels of aflatoxin B1. For more information see https://kmthepatech.com/toxicity-of-aflatoxin-b1-in-vitro-and-in-vivo/

Morita, K. et al. Sci Rep. 2020; 10(1):13139. https://pubmed.ncbi.nlm.nih.gov/32753643/

“Decomposition profile data analysis of multiple drug effects identifies endoplasmic reticulum stress‑inducing ability as an unrecognized factor”

Morita et al. focused on the ability of drugs to induce endoplasmic reticulum (ER) stress. Some drugs overwhelm relevant compensatory machinery and can cause drug-induced liver injury (DILI). Induction of ER stress was studies in MCF7 cells and compared to PXB-cells®, HepG2 and HuH7. PXB-cells® were selected because their normal metabolic activities and reactivity to compounds are relatively well preserved compared to those of hepatic cancer-derived cell lines (HepG2 and HuH7). Thus, the study of manifestations of ER stress induced by the candidate drugs was expected to be more relevant in PXB-cells®.

Kohara, H. et al. Toxicol Sci. 2020; 173 (2), 347-361. https://pubmed.ncbi.nlm.nih.gov/31722436/

Cholestasis and DILI schematic

“High-throughput screening to evaluate inhibition of bile acid transporters using human hepatocytes isolated from chimeric mice”

Kohara et al. discuss that cholestasis resulting from hepatic bile acid efflux transporter inhibition may contribute to drug induced liver injury (DILI). Authors showed that in terms of gene expression comparison, PXB-cells resembled human liver tissue more closely than HepaRG or HepG2 cells at all time points tested and still became closer to human liver tissue throughout the culture period. The ADME gene expression of PXB-cells® became closer to that of human liver tissue over time, whereas PHHs did not become closer.

 

The summary is prepared by Dr. S. Sapelnikova.