title: The Uremic Toxin Indoxyl-3-Sulfate Induces CYP1A2 In Primary Human Hepatocytes.
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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Nonclinical Development, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA.
authors.forename: Rangaraj
authors.initials: R
authors.lastname: Narayanan
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007200:Indican / Q000008:administration & dosage / Q000494:pharmacology*; D007210:Indoleacetic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology; D014511:Uremia / Q000503:physiopathology
chemical_list: D007210:Indoleacetic Acids; D012333:RNA, Messenger; C030737:indoleacetic acid; D019388:Cytochrome P-450 CYP1A2; D009853:Omeprazole; D007200:Indican