Abstract
Drug-induced phospholipidosis (PL) is a storage disorder caused by the formation of phospholipid-drug complexes in lysosomes. Because of the diversity of PL between species, human cell-based assays have been used to predict drug-induced PL in humans. We established three-dimensional (3D) human liver organoids as described previously and investigated their liver characteristics through multiple analyses. Drug-induced PL was initiated in these organoids and in monolayer HepG2 cultures, and cellular changes were systemically examined. Organoids that underwent differentiation showed characteristics of hepatocytes rather than HepG2 cells. The organoids also survived under PL-inducing drug conditions for 48 h and maintained a more stable albumin secretion level than the HepG2 cells. More cytoplasmic vacuoles were observed in organoids and HepG2 cells treated with more potent PL-induced drugs, but to a greater extent in organoids than in HepG2 cells. Lysosome-associated membrane protein 2, a marker of lysosome membranes, showed a stronger immunohistochemical signal in the organoids. PL-distinctive lamellar bodies were observed only in amiodarone-treated organoids by transmission electron microscopy. Human liver organoids are thus more sensitive to drug-induced PL and less affected by cytotoxicity than HepG2 cells. Since PL is a chronic condition, these results indicate that organoids better reflect metabolite-mediated hepatotoxicity in vivo and could be a valuable system for evaluating the phospholipidogenic effects of different compounds during drug development.
Highlights
Drug-induced phospholipidosis (PL) is a phospholipid storage disorder caused by the formation of phospholipid-drug complexes in lysosomes, characterized as lamellar bodies by transmission electron microscopy [1]
The results indicate that organoids better reflect metabolite-mediated hepatotoxicity in vivo and could be a valuable system for evaluating the phospholipidogenic effects of different compounds during drug development
Our findings indicate the feasibility of organoids to predict and screen out the phospholipidosis
Summary
Drug-induced phospholipidosis (PL) is a phospholipid storage disorder caused by the formation of phospholipid-drug complexes in lysosomes, characterized as lamellar bodies by transmission electron microscopy [1]. The controversy continues over whether PL is a toxic or adaptive response. PL is generally considered to be an adaptive response rather than an adverse effect of a particular drug at the early stages [6]. Due to the uncertainty of the toxicological outcome of PL, drug-induced PL discovered in preclinical studies can have a detrimental impact on pharmaceutical development and delay the process. Fatal genetic disorders such as Niemann–Pick disease and Tay–Sachs disease [9,10] associated with PL have been described in humans, as has cell membrane damage leading to cell death. Other hepatic [11,12] cardiac [13,14], renal [15,16] pulmonary [17,18], eye [19], nervous [20], and skin [21] toxicities related to PL are known
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
