Abstract：
:From routine in vitro drug-transporter inhibition assays, observed inhibition is typically assumed from direct interaction with the transporter. Other mechanisms that possibly reduce substrate uptake are not frequently fully examined. The objective of this study was to investigate the association of transporter inhibition with drug cytotoxicity. From a pool of drugs that were identified as known ASBT or OCTN2 inhibitors, 21 drugs were selected to screen inhibitory potency of their prototypical substrate and cytotoxicity against three human sodium-dependent solute carrier (SLC) transporters: apical sodium-dependent bile acid transporter (ASBT), organic cation/carnitine transporter (OCTN2), and the excitatory amino acid transporter 4 (EAAT4) in stable cell lines. Twenty drugs showed apparent inhibition in OCTN2-MDCK and ASBT-MDCK. Four dihydropyridine calcium channel blockers were cytotoxic to MDCK cells, and the observed cytotoxicity of three of them accounted for their apparent OCTN2 inhibition, and consequently were classified as non-OCTN2 inhibitors. Meanwhile, since their cytotoxicity only moderately contributed to ASBT inhibition, these three were still considered ASBT inhibitors. Four other drugs showed apparent inhibition in EAAT4-HEK cells, and cytotoxicity of three drugs corresponded with their inhibition of this transporter. Therefore, cytotoxicity significantly affected EAAT4 observations. Results showed the potential of cytotoxicity as a mechanism that can account for apparent in vitro transporter inhibition. Drug cytotoxicity varied in different cell lines, which could increase false positives for pharmacophore development.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Zheng X,Diao L,Ekins S,Polli JEdoi
10.1016/j.bcp.2010.06.012subject
Has Abstractpub_date
2010-10-01 00:00:00pages
1087-92issue
7eissn
0006-2952issn
1873-2968pii
S0006-2952(10)00446-6journal_volume
80pub_type
杂志文章abstract：:Incorporation of thia fatty acids and their effects on the fatty acid composition in phospholipids has been investigated in 7800 C1 hepatoma cells and cultured hepatocytes. 3-Thia fatty acids of chain lengths from dodecyl-to hexadecyl-thioacetic acid were incorporated into phospholipids during a 3-day incubation. Long...
journal_title：Biochemical pharmacology
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doi：10.1016/0006-2952(95)02182-5
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(90)90093-z
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pub_type： 杂志文章
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pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(85)90106-6
更新日期：1985-01-01 00:00:00
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pub_type： 杂志文章
doi：10.1016/s0006-2952(98)00075-6
更新日期：1998-06-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1989-09-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(96)00343-7
更新日期：1996-08-23 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(97)82443-4
更新日期：1997-05-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(86)90073-0
更新日期：1986-03-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.bcp.2005.12.019
更新日期：2006-05-28 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2004.02.028
更新日期：2004-07-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(94)90210-0
更新日期：1994-10-18 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：2010-03-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(86)90699-4
更新日期：1986-12-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1992-07-07 00:00:00
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pub_type： 杂志文章
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更新日期：2014-12-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1990-08-15 00:00:00
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更新日期：2003-03-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：2011-03-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：2000-07-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1997-10-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：2006-12-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2015.09.021
更新日期：2015-12-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2007.07.021
更新日期：2007-10-15 00:00:00
abstract：:Vindesine biotransformation was investigated using a bank of human liver microsomes. The drug was converted into one major metabolite (M) upon incubation with the microsomes. Large interindividual variations were observed: vindesine biotransformation rates ranged from 1.2 to 12.9 pmol/min/mg protein. Vindesine metabol...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(93)90169-w
更新日期：1993-02-24 00:00:00
