The role of cytochrome P450 3A4-mediated metabolism in sorafenib and lapatinib hepatotoxicity.

Autor:	McGill MR; Dept. of Environmental Health Sciences, Fay W. Boozman College of Public Health; Depts. of Pharma-cology & Toxicology and Pathology, College of Medicine; University of Arkansas for Medical Sciences, Little Rock, AR, 72205 USA., Kaufman YJ; Dept. of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 USA., LoBianco FV; Dept. of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 USA., Schleiff MA; Dept. of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 USA., Aykin-Burns N; Dept. of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 USA., Miller GP; Dept. of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205 USA.
Jazyk:	angličtina
Zdroj:	Livers [Livers] 2023 Jun; Vol. 3 (2), pp. 310-321. Date of Electronic Publication: 2023 Jun 19.
DOI:	10.3390/livers3020022
Abstrakt:	Tyrosine kinase inhibitors (TKIs) are increasingly popular drugs used to treat more than a dozen different diseases, including some forms of cancer. Despite having fewer adverse effects than traditional chemotherapies, they are not without risks. Liver injury is a particular concern. Of the FDA-approved TKIs, approximately 40% cause hepatotoxicity. However, little is known about the underlying pathophysiology. The leading hypothesis is that TKIs are converted by cytochrome P450 3A4 (CYP3A4) to reactive metabolites that damage proteins. Indeed, there is strong evidence for this bioactivation of TKIs in in vitro reactions. However, the actual toxic effects are underexplored. Here, we measured the cytotoxicity of several TKIs in primary mouse hepatocytes, HepaRG cells, and HepG2 cells with and without CYP3A4 modulation. To our surprise, the data indicate that CYP3A4 increases resistance to sorafenib and lapatinib hepatotoxicity. The results have implications for the mechanism of toxicity of these drugs in patients and underline the importance of selecting an appropriate experimental model. Competing Interests: Conflicts of Interest: M.R.M. has consulted for Alkermes, GlaxoSmithKline, and Acetaminophen Toxicity Diagnostics, LLC, and has received research funding from GlaxoSmithKline for an un-related project. These companies had no role in the conception, design, approval, execution, or funding of this study, nor in the decision to publish. The other authors declare no competing interests.
Databáze:	MEDLINE
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