The Uremic Toxin Indoxyl-3-Sulfate Induces CYP1A2 In Primary Human Hepatocytes

Author(s): Hong Liu, Rangaraj Narayanan, Matthew Hoffmann, Sekhar Surapaneni

Journal Name: Drug Metabolism Letters

Volume 10 , Issue 3 , 2016

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Graphical Abstract:


Chronic kidney disease (CKD) generally impacts clearance of renally eliminated drugs but growing evidence shows that it can influence clearance of hepatically eliminated drugs and a complete mechanistic understanding of this phenomenon is still lacking. CKD leads to accumulation of uremic toxins, including indoxyl- 3-sulfate (3-INDS) and indole-3-acetic acid (3-IAA).

Objective: In this study, we evaluated the potential of 3-INDS and 3-IAA (10, 30 and 100 μM) to induce liver cytochrome P450 (CYP) enzymes CYP1A2, 2B6 and 3A4/5 using cultured primary human hepatocytes following once daily treatment for 3 days.

Results: 3-INDS potently induced CYP1A2 mRNA and enzyme activity in a dose-dependent manner but did not induce CYP2B6 or 3A4. At 100 μM, a concentration observed in humans under uremic conditions, 3-INDS increased CYP1A2 mRNA and activity by 93% and 292% respectively when compared with prototypical inducer omeprazole. However, 3-IAA did not induce CYP1A2, 2B6 or 3A4.

Conclusion: These results suggest that the uremic toxin, 3-INDS, is a potent CYP1A2 inducer and lends valuable mechanistic basis for how kidney disease can affect hepatic metabolism.

Keywords: Chronic kidney disease, chronic renal failure, cytochrome P450, high-performance liquid chromatography, indole- 3-acetic acid, indoxyl-3-sulfate, liquid chromatography-tandem mass spectrometry.

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Article Details

Year: 2016
Published on: 28 September, 2016
Page: [195 - 199]
Pages: 5
DOI: 10.2174/1872312810666160719143703

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