Opportunities and challenges in using human hepatocytes in cytochromes P450 induction assays

ABSTRACT

Introduction: Identification of inducers of xenobiotic-metabolizing cytochromes P450 (CYP) is of topical interest. The issue mainly concerns three sectors: (i) preclinical testing of drug candidates and testing existing drugs and their combinations; (ii) food safety applications with regard to additives, contaminants, and adulterants; (iii) environmental applications, comprising detection and identification of endocrine disruptors.

Areas covered: A literature search was performed using the PubMed database, covering state-of-the-art of human hepatocyte (HH) culture use, and their exploitation for the identification of P450 inducers. A list of CYP inducers identified by HHs is provided.

Expert opinion: Primary cultures of HHs had long been considered as a gold standard for induction assays of xenobiotic-metabolizing enzymes. Owing to several shortcomings of HHs, alternative approaches such as immortalization of HHs, use of cell lines, generation of clonal cell lines from HHs, use of induced pluripotent stem (iPS) cells, cells from humanized animals, etc., were employed. While yielding particular advantage, overall, alternatives to HHs still remain an avenue for discrete applications or technical situations. Thus, HHs remain the most suitable model for complex CYP induction studies. The summary may be effectively expressed by strength/weakness/opportunity/threats analysis.

KEYWORDS:

• Drug–drug interactions
• drug-metabolizing enzymes
• gene induction
• human hepatocytes

Article highlights.

• Human hepatocytes (HHs) are the gold standard for induction assays of xenobiotic metabolizing P450s.

• HHs provide the opportunity to study induction of phase II enzymes and xenobiotic transporters.

• HHs have complex signaling and metabolizing pathways, providing a highly physiological model.

• HHs allow studying the effects of metabolites and maternal drugs simultaneously.

• HHs avoid interspecies differences, which are important in the induction process.

This box summarizes key points contained in the article.

Declaration of interest

The author was supported by grants from the Czech Science Foundation GACR 303/12/G163 and Ministry of Health of the Czech Republic NT/13591. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.