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Cited by 104Pharmacogenetics and Drug MetabolismDrug Transport and Resistance MechanismsDrug-Induced Hepatotoxicity and Protection

Cross-species analysis of hepatic cytochrome P450 and transport protein expression

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Hammer, Helen, Schmidt, Felix, Marx-Stoelting, Philip, Pötz, Oliver, Braeuning, Albert·2021·Archives of Toxicology
DOI 10.1007/s00204-020-02939-4PMC PMC7811513
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Abstract

Most drugs and xenobiotics are metabolized in the liver. Amongst others, different cytochrome P450 (CYP) enzymes catalyze the metabolic conversion of foreign compounds, and various transport proteins are engaged in the excretion of metabolites from the hepatocytes. Inter-species and inter-individual differences in the hepatic levels and activities of drug-metabolizing enzymes and transporters result from genetic as well as from environmental factors, and play a decisive role in determining the pharmacokinetic properties of a compound in a given test system. To allow for a meaningful comparison of results from metabolism studies, it is, therefore, of utmost importance to know about the specific metabolic properties of the test systems, especially about the levels of metabolic enzymes such as the CYPs. Using a targeted proteomics approach, we, therefore, compared the hepatic levels of important CYP enzymes and transporters in different experimental systems in vivo and in vitro, namely Wistar rats, C57/Bl6 mice, mice humanized for the two xeno-sensing receptors PXR (pregnane-X-receptor) and CAR (constitutive androstane receptor), mice with human hepatocyte-repopulated livers, human HepaRG hepatocarcinoma cells, primary human hepatocytes, and human liver biopsies. In addition, the effects of xenobiotic inducers of drug metabolism on CYP enzymes and transporters were analyzed in selected systems. This study for the first time presents a comprehensive overview of similarities and differences in important drug metabolism-related proteins among the different experimental models.

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  • Major human CYP450 drug-metabolizing isoenzymes (CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2) lack direct orthologs in mice.

    “The major human isoenzymes of drug metabolism (CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2) lack direct orthologs in mice.”

    From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [53]

    Results, Table 1 is titled “Selected orthologous CYP proteins in human, rat and mouse” and lists mouse counterparts for CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Its mouse entry for CYP3A4 is blank, so the paper does not support the claim that all five lack direct mouse orthologs. Page numbers were not supplied in our copy. (LLM, conf=0.90)

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Cited by

Sorted by citations

Authors
Hammer, H., Schmidt, F., Marx-Stoelting, P., Pötz, O., & Braeuning, A.
Affiliations
  • Signatope GmbH (Germany) (DE)
  • German Federal Institute for Risk Assessment (BfR) (DE)
Corresponding author
Braeuning, Albert
ORCID
Venue
Archives of Toxicology
Publisher
Springer Science and Business Media LLC
Published
2020-11-04
Volume
95
Issue
1
Pages
117-133
ISSN
  • 0340-5761 (ISSN-L)
  • 1432-0738
DOI
10.1007/s00204-020-02939-4
PMC
PMC7811513
OpenAlex
W3094851849
Cited by
104
References
3
Citations by year
2026: 17 · 2025: 22 · 2024: 14 · 2023: 20 · 2022: 20 · 2021: 11
FWCI
11.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Archives of Toxicology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion)
  • OpenAgrar (submittedVersion, cc-by)
Funders
  • Bundesinstitut für Risikobewertung (1322-499)
  • Bundesinstitut für Risikobewertung (BfR)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
cytochrome P450, drug transporters, hepatic drug metabolism, cross-species comparison, pregnane X receptor, humanized mice, HepaRG cells, primary human hepatocytes, in vitro liver models, pharmacokinetics
MeSH terms
Pregnane X Receptor, Constitutive Androstane Receptor, Animals, Biological Transport, Biotransformation, Cell Line, Cytochrome P-450 Enzyme System, Pharmaceutical Preparations, Humans, Isoenzymes, Liver, Mice, Inbred C57BL, Species Specificity, Substrate Specificity, Xenobiotics, Rats, Wistar, Receptors, Cytoplasmic and Nuclear, Membrane Transport Proteins, Mice, Rats

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