Through a glass, darkly? HepaRG and HepG2 cells as models of human phase I drug metabolism

Lesley A. Stanley (Lead / Corresponding author), C. Roland Wolf

Research output: Contribution to journalReview articlepeer-review

13 Citations (Scopus)
95 Downloads (Pure)

Abstract

The pharmacokinetic and safety assessment of drug candidates is becoming increasingly dependent upon in vitro models of hepatic metabolism and toxicity. Predominant among these is the HepG2 cell line, although HepaRG is becoming increasingly popular because of its perceived closer resemblance to human hepatocytes. We review the functionality of these cell lines in terms of Phase I protein expression, basal cytochrome P450-dependent activity, and utility in P450 induction studies. Our analysis indicates that HepG2 cells are severely compromised: proteomic studies show that they express few key proteins in common with hepatocytes and they lack drug-metabolizing capacity. Differentiated HepaRGs are more hepatocyte-like than HepG2s, but they also have limitations, and it is difficult to assess their utility because of the enormous variability in data reported, possibly arising from the complex differentiation protocols required to obtain hepatocyte-like cells. This is exacerbated by the use of DMSO in the induction protocol, together with proprietary supplements whose composition is a commercial secret. We conclude that, while currently available data on the utility of HepaRG generates a confusing picture, this line does have potential utility in drug metabolism studies. However, to allow studies to be compared directly a standardized, reproducible differentiation protocol is essential and the cell line's functionality in terms of known mechanisms of P450 regulation must be demonstrated. We, therefore, support the development of regulatory guidelines for the use of HepaRGs in induction studies as a first step in generating a database of consistent, reliable data.

Original languageEnglish
Pages (from-to)46-62
Number of pages17
JournalDrug Metabolism Reviews
Volume54
Issue number1
Early online date23 Feb 2022
DOIs
Publication statusPublished - 2022

Keywords

  • CYP2B6
  • CYP3A4
  • HepG2
  • HepaRG
  • constitutive androstane receptor
  • cytochrome P450
  • drug-drug interaction
  • hepatocytes
  • in vitro techniques
  • pregnane X receptor

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology (medical)

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