Novel Bile Acid-Dependent Mechanisms of Hepatotoxicity Associated with Tyrosine Kinase Inhibitors

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Fältnamn	Indikatorer	Metadata
000		05123naa a2200373 4500
001		oai:DiVA.org:uu-470569
003		SwePub
008		220328s2022 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4705692 URI
024	7	a https://doi.org/10.1124/jpet.121.0008282 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Saran, Chitrau Univ N Carolina, UNC Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA.;Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, CB 7569,Kerr Hall, Chapel Hill, NC 27599 USA.4 aut
245	1 0	a Novel Bile Acid-Dependent Mechanisms of Hepatotoxicity Associated with Tyrosine Kinase Inhibitors
264		c 2021-11-18
264	1	b American Society for Pharmacology & Experimental Therapeutics (ASPET),c 2022
338		a print2 rdacarrier
520		a Drug-induced liver injury (DILI) is the leading cause of acute liver failure and a major concern in drug development. Altered bile acid homeostasis via inhibition of the bile salt export pump (BSEP) is one mechanism of DILI. Dasatinib, pazopanib, and sorafenib are tyrosine kinase inhibitors (TKIs) that competitively inhibit BSEP and increase serum biomarkers for hepatotoxicity in similar to 25-50% of patients. However, the mechanism(s) of hepatotoxicity beyond competitive inhibition of BSEP are poorly understood. This study examined mechanisms of TKI-mediated hepatotoxicity associated with altered bile acid homeostasis. Dasatinib, pazopanib, and sorafenib showed bile acid-dependent toxicity at clinically relevant concentrations, based on the C-DILI assay using sandwich-cultured human hepatocytes (SCHH). Among several bile acid-relevant genes, cytochrome P450 (CYP) 7A1 mRNA was specifically upregulated by 6.2- to 7.8-fold (dasatinib) and 5.7-to 9.3-fold (pazopanib), compared with control, within 8 hours. This was consistent with increased total bile acid concentrations in culture medium up to 2.3-fold, and in SCHH up to 1.4-fold, compared with control, within 24 hours. Additionally, protein abundance of sodium tauro cholate co-transporting polypeptide (NTCP) was increased up to 2.0-fold by these three TKIs. The increase in NTCP protein abundance correlated with increased function; dasatinib and pazopanib increased hepatocyte uptake clearance (CLuptake) of taurocholic acid, a probe bile acid substrate, up to 1.4-fold. In conclusion, upregulation of CYP7A1 and NTCP in SCHH constitute novel mechanisms of TKI-associated hepatotoxicity. SIGNIFICANCE STATEMENT Understanding the mechanisms of hepatotoxicity associated with tyrosine kinase inhibitors (TKIs) is fundamental to development of effective and safe intervention therapies for various cancers. Data generated in sandwich-cultured human hepatocytes, an in vitro model of drug-induced hepatotoxicity, revealed that TKIs upregulate bile acid synthesis and alter bile acid uptake and excretion. These findings provide novel insights into additional mechanisms of bile acid-mediated drug-induced liver injury, an adverse effect that limits the use and effectiveness of TKI treatment in some cancer patients.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Gastroenterologi0 (SwePub)302132 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Gastroenterology and Hepatology0 (SwePub)302132 hsv//eng
700	1	a Sundqvist, Louiseu Uppsala universitet,Institutionen för farmaci,Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, CB 7569,Kerr Hall, Chapel Hill, NC 27599 USA.4 aut
700	1	a Ho, Henryu Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, CB 7569,Kerr Hall, Chapel Hill, NC 27599 USA.4 aut
700	1	a Niskanen, Jonnau Univ Eastern Finland, Sch Pharm, Kuopio, Finland.4 aut
700	1	a Honkakoski, Paavou Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, CB 7569,Kerr Hall, Chapel Hill, NC 27599 USA.;Univ Eastern Finland, Sch Pharm, Kuopio, Finland.4 aut
700	1	a Brouwer, Kim L. R.u Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, CB 7569,Kerr Hall, Chapel Hill, NC 27599 USA.4 aut
710	2	a Univ N Carolina, UNC Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA.;Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, CB 7569,Kerr Hall, Chapel Hill, NC 27599 USA.b Institutionen för farmaci4 org
773	0	t Journal of Pharmacology and Experimental Therapeuticsd : American Society for Pharmacology & Experimental Therapeutics (ASPET)g 380:2, s. 114-125q 380:2<114-125x 0022-3565x 1521-0103
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-470569
856	4 8	u https://doi.org/10.1124/jpet.121.000828

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