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Detection of statin cytotoxicity is increased in cells expressing the OATP1B1 transporter.
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- Author(s): Zhang X;Zhang X; Scialis RJ; Feng B; Leach K
- Source:
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2013 Jul; Vol. 134 (1), pp. 73-82. Date of Electronic Publication: 2013 Apr 05.
- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't
- Language:
English
- Additional Information
- Source:
Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE
- Publication Information:
Publication: 1999- : Cary, NC : Oxford University Press
Original Publication: Orlando, FL : Academic Press, c1998-
- Subject Terms:
- Abstract:
Cytotoxicity of a compound is determined by the intracellular concentration mediated both by passive permeability and active uptake through drug transporters. However, the major liver uptake transporters were either absent or expressed at significantly lower levels in human liver cell lines than in human liver. When comparing cytotoxicity of five statins, the organic anion transporting polypeptide 1B1 expressing HEK cells showed a significantly higher sensitivity than the wild-type HEK cells. The IC50 shifts ranged from 9- to >100-fold, and the potency shifts collapsed in the presence of rifampicin, the inhibitor for OATPs. The extent of the IC50 shift correlated with the permeability of the statins with high permeable compounds having smaller shifts and low permeable compounds having larger shifts. The changes in statin potency in transporter-transfected cells reflect the active uptake of statins into the cells, and the increased intracellular drug concentration lead to increased toxicity. The data suggested that uptake transporters have a significant impact on the outcomes of a cell-based assay and should be considered during the early stages of compound toxicity screening in drug discovery. For compounds with low permeability that are likely to undergo transporter-mediated uptake, it is important to test them in transporter-competent cell models.
- Contributed Indexing:
Keywords: OATP1B1; cytotoxicity; permeability; statin; uptake transporter
- Accession Number:
0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
0 (Liver-Specific Organic Anion Transporter 1)
0 (Organic Anion Transporters)
0 (SLCO1B1 protein, human)
VJT6J7R4TR (Rifampin)
- Publication Date:
Date Created: 20130409 Date Completed: 20140128 Latest Revision: 20181203
- Publication Date:
20240829
- Accession Number:
10.1093/toxsci/kft085
- Accession Number:
23564645
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