title: Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies.
abstract: Gender, ethnicity and individual differences in hepatic metabolism have major impact on individual drug response, adverse events and attrition rate during drug development. Therefore, there is an urgent need for reliable test systems based on human cells. Yet, the use of primary human hepatocytes (PHHs) is restricted by limited availability, invasive preparation and short-term stability in culture. All other cellular approaches proposed so far have major disadvantages. We investigated whether peripheral human monocytes after cultivation according to our novel protocol (monocyte-derived hepatocyte-like cells (MH cells)) can serve as an in vitro model for hepatocyte metabolism. Enzyme activities, synthesis parameters (coagulation factor VII and urea) and cytochrome (CY) P450 activities and induction were investigated. Furthermore, MH cells were compared with PHH from the same donor. Using our protocol, we could generate cells that exhibit hepatocyte-like properties: These cells show 71±9% of specific ALT activity, 41±3% of CYP3A4 activity and 65±13% of factor VII secretion when compared with PHHs. Consequently, CYP-mediated acetaminophen toxicity and drug interactions could be shown. Moreover, the investigated parameters were stable in culture over at least 4 weeks. Furthermore, MH cells retain gender-specific and donor-specific CYP activities and toxicity profiles, respectively. MH cells show quantitative and qualitative approximation to human hepatocytes concerning CYP-metabolism and toxicity. Our data support individual prediction of toxicity and CYP metabolism. MH cells are a novel tool to investigate long-term hepatic toxicity, metabolism and drug interactions.
authors.affiliation: Department of Internal Medicine II, University Hospital Grosshadern, Ludwigs-Maximilians-University Munich, Munich, Germany. andreas.benesic@med.uni-muenchen.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Benesic
authors.forename: Nora L
authors.initials: NL
authors.lastname: Rahm
authors.forename: Samuel
authors.initials: S
authors.lastname: Ernst
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerbes
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000410:Alanine Transaminase / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005167:Factor VII / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D057285:Precision Medicine / Q000379:methods*; D012737:Sex Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; D000082:Acetaminophen; D005167:Factor VII; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000410:Alanine Transaminase