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

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

Volume: 10 Issue: 3

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

Affiliation:

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.

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.

Cite this article as:

Liu Hong, Narayanan Rangaraj, Hoffmann Matthew and Surapaneni Sekhar, The Uremic Toxin Indoxyl-3-Sulfate Induces CYP1A2 In Primary Human Hepatocytes, Drug Metabolism Letters 2016; 10 (3) . https://dx.doi.org/10.2174/1872312810666160719143703