Chemically induced hepatotoxicity in human stem cell-induced hepatocytes compared with primary hepatocytes and HepG2.
Stem cell-induced hepatocytes (SC-iHeps) have been suggested as a valuable model for evaluating drug toxicology. Here, human-induced pluripotent stem cells (QIA7) and embryonic stem cells (WA01) were differentiated into hepatocytes, and the hepatotoxic effects of acetaminophen (AAP) and aflatoxin B1 (AFB1) were compared with primary hepatocytes (p-Heps) and HepG2. In a cytotoxicity assay, the IC50 of SC-iHeps was similar to that in p-Heps and HepG2 in the AAP groups but different from that in p-Heps of the AFB1 groups. In a multi-parameter assay, phenotypic changes in mitochondrial membrane potential, calcium influx and oxidative stress were similar between QIA7-iHeps and p-Heps following AAP and AFB1 treatment but relatively low in WA01-iHeps and HepG2. Most hepatic functional markers (hepatocyte-specific genes, albumin/urea secretion, and the CYP450 enzyme activity) were decreased in a dose-dependent manner following AAP and AFB1 treatment in SC-iHeps and p-Heps but not in HepG2. Regarding CYP450 inhibition, the cell viability of SC-iHeps and p-Heps was increased by ketoconazole, a CYP3A4 inhibitor. Collectively, SC-iHeps and p-Heps showed similar cytotoxicity and hepatocyte functional effects for AAP and AFB1 compared with HepG2. Therefore, SC-iHeps have phenotypic characteristics and sensitivity to cytotoxic chemicals that are more similar to p-Heps than to HepG2 cells.
Veterinary Drugs and Biologics Division, Animal and Plant Quarantine Agency, 480, Anyang 6-dong, Anyang, 430-824, Gyeonggi-do, Republic of Korea.
Seok-Jin
SJ
Kang
Veterinary Drugs and Biologics Division, Animal and Plant Quarantine Agency, 480, Anyang 6-dong, Anyang, 430-824, Gyeonggi-do, Republic of Korea.
Hyuk-Mi
HM
Lee
Veterinary Drugs and Biologics Division, Animal and Plant Quarantine Agency, 480, Anyang 6-dong, Anyang, 430-824, Gyeonggi-do, Republic of Korea.
Young-Il
YI
Park
Veterinary Drugs and Biologics Division, Animal and Plant Quarantine Agency, 480, Anyang 6-dong, Anyang, 430-824, Gyeonggi-do, Republic of Korea.
Hee
H
Yi
CHEM.I.NET Ltd, Mok-dong, Yangcheon-gu, Seoul, 158-818, Republic of Korea.
Hunjoo
H
Lee
Veterinary Drugs and Biologics Division, Animal and Plant Quarantine Agency, 480, Anyang 6-dong, Anyang, 430-824, Gyeonggi-do, Republic of Korea.
ByungJae
B
So
Veterinary Drugs and Biologics Division, Animal and Plant Quarantine Agency, 480, Anyang 6-dong, Anyang, 430-824, Gyeonggi-do, Republic of Korea.
Jae-Young
JY
Song
Veterinary Drugs and Biologics Division, Animal and Plant Quarantine Agency, 480, Anyang 6-dong, Anyang, 430-824, Gyeonggi-do, Republic of Korea. kanghg67@korea.kr.
Hwan-Goo
HG
Kang
D000082:Acetaminophen / Q000494:pharmacology; D016604:Aflatoxin B1 / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003603:Cytotoxins / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects; D061251:Primary Cell Culture; D018675:Toxicity Tests / Q000379:methods
D003603:Cytotoxins; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1
HepG2; Hepatotoxicity; Primary hepatocyte; Stem cell-induced hepatocyte