RRC ID 72237
Author Takemura A, Gong S, Sato T, Kawaguchi M, Sekine S, Kazuki Y, Horie T, Ito K.
Title Evaluation of Parent- and Metabolite-Induced Mitochondrial Toxicities Using CYP-Introduced HepG2 cells.
Journal J Pharm Sci
Abstract Mitochondrial toxicity is an important factor to predict drug-induced liver injury (DILI). Previous studies have focused predominantly on mitochondrial toxicities due to parent forms, and no study has adequately evaluated metabolite-induced mitochondrial toxicity. Moreover, previous studies have used HepG2 cells, which lack many cytochrome P450 (CYP) genes. To overcome this problem, CYP-introduced HepG2 cells were constructed using several gene transfer technologies, including adenoviruses and plasmids. However, these methods only led to a transient expression of CYP genes. In the present study, usefulness of four CYPs introduced-HepG2 (TC-Hep) cells previously constructed through mammalian artificial chromosome technology were examined, especially from the perspective of mitochondrial toxicity. First, we evaluated the effects of known compounds, such as rotenone and flutamide, on mitochondrial toxicity and cell death in TC-Hep cells cultured in galactose conditions. Expectedly, rotenone-induced cell death ameliorated because rotenone was metabolized by CYPs into inactive form(s) and flutamide-induced cell death increased in TC-Hep cells. Second, we evaluated five compounds that caused liver injury in clinical phase and were discontinued during pharmaceutical development. The present in vitro tool suggested that three of the five compounds caused metabolite-induced mitochondrial toxicities. In conclusion, the present in vitro tool could easily and inexpensively detect metabolite-induced mitochondrial toxicity; hence, it can be useful for predicting DILI in preclinical phase.
Volume 110(9)
Pages 3306-3312
Published 2021-9-1
DOI 10.1016/j.xphs.2021.06.001
PII S0022-3549(21)00291-4
PMID 34097978
MeSH Animals Chemical and Drug Induced Liver Injury* Cytochrome P-450 Enzyme System* Hep G2 Cells Humans Parents
IF 2.997
Human and Animal Cells Hep G2(RCB1648)