title: Inhibition of human drug-metabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins.
abstract: OBJECTIVE
  To investigate the potential inhibitory effects of uremic toxins on the major human hepatic drug-metabolising cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes in vitro.
  
  
  METHODS
  Benzyl alcohol, p-cresol, indoxyl sulfate, hippuric acid and a combination of the four uremic toxins were co-incubated with human liver microsomes and selective probe substrates for the major human drug-metabolising CYP and UGT enzymes. The percentage of enzyme inhibition was calculated by measuring the rates of probe metabolite formation in the absence and presence of the uremic toxins. Kinetics studies were conducted to evaluate the K i values and mechanism(s) of the inhibition of CYP2E1, CYP3A4, UGT1A1 and UGT1A9 by p-cresol.
  
  
  RESULTS
  The individual uremic toxins inhibited CYP and UGT enzymes to a variable extent. p-Cresol was the most potent individual inhibitor, producing >50% inhibition of CYP2E1, CYP3A4, UGT1A1, UGT1A9 and UGT2B7 at a concentration of 100 μM. The greatest inhibition was observed with UGT1A9. p-Cresol was shown to be an uncompetitive inhibitor of UGT1A9, with unbound K i values of 9.1 and 2.5 μM in the absence and presence of bovine serum albumin (BSA), respectively. K i values for p-cresol inhibition of human liver microsomal CYP2E1, CYP3A4 and UGT1A1 ranged from 43 to 89 μM. A combination of the four uremic toxins produced >50% decreases in the activities of CYP1A2, CYP2C9, CYP2E1, CYP3A4, UGT1A1, UGT1A9 and UGT2B7.
  
  
  CONCLUSIONS
  Uremic toxins may contribute to decreases in drug hepatic clearance in individuals with kidney disease by inhibition of hepatic drug-metabolising enzymes.
authors: Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre, Sturt Rd, Bedford Park, Adelaide, SA, 5042, Australia.
authors: Kyra J
authors: KJ
authors: Barnes
authors: Andrew
authors: A
authors: Rowland
authors: Thomas M
authors: TM
authors: Polasek
authors: John O
authors: JO
authors: Miners
mesh_terms: D019905:Benzyl Alcohol / Q000494:pharmacology; D003408:Cresols / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006626:Hippurates / Q000494:pharmacology; D006801:Humans; D007200:Indican / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D014118:Toxins, Biological / Q000494:pharmacology*; D014511:Uremia
chemical_list: D003408:Cresols; D065607:Cytochrome P-450 Enzyme Inhibitors; D006626:Hippurates; D014118:Toxins, Biological; C032538:4-cresol; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D019905:Benzyl Alcohol; D007200:Indican; C030514:hippuric acid