Cytochrome P-450 1A1 expression in human small bowel: interindividual variation and inhibition by ketoconazole

Drug Metab Dispos. 1999 Mar;27(3):360-4.

Abstract

Human cytochrome P-450 1A1 (CYP1A1) is located primarily in extrahepatic tissues. To begin the characterization of this enzyme in the small intestine, we screened a bank of 18 human small intestinal microsomal preparations for CYP1A1 catalytic [(7-ethoxyresorufin O-deethylase (EROD)] activity and protein content. Although EROD activity was below detectable limits in 12 of the preparations, 6 exhibited measurable activity (1.4-123.5 pmol/min/mg), some exceeding that for 2 human liver microsomal preparations (11.0 and 26.4 pmol/min/mg). This variation was not due to variable quality of the preparations because each sample displayed readily detectable CYP3A4 catalytic activity and immunoreactive protein. We inadvertently found that intestinal EROD activity was inhibitable by ketoconazole at a concentration commonly believed to selectively inhibit CYP3A4. The possibility that CYP3A4 metabolizes 7-ethoxyresorufin was excluded because there was no correlation between intestinal CYP3A4 catalytic and EROD activity, and cDNA-expressed human CYP3A4 exhibited no EROD activity. Moreover, CYP1A1 immunoreactive protein was most abundant in the three intestinal preparations with the highest EROD activities, and the mean apparent Ki of ketoconazole observed for these three preparations (40 nM) was essentially identical with that for cDNA-expressed human CYP1A1 (37 nM). In summary, there is large interindividual variation in CYP1A1 expression in human small bowel, and ketoconazole is not a selective CYP3A4 inhibitor in in vitro metabolism studies involving intestinal tissue obtained from some individuals. These observations raise the possibility that in vivo drug interactions involving ketoconazole could result from CYP1A1 inhibition in the intestine in some individuals.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Western
  • Caco-2 Cells / enzymology
  • Cytochrome P-450 CYP1A1 / antagonists & inhibitors*
  • Cytochrome P-450 CYP1A1 / biosynthesis*
  • Cytochrome P-450 CYP1A1 / metabolism
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Intestine, Small / drug effects*
  • Intestine, Small / enzymology*
  • Ketoconazole / pharmacology*
  • Microsomes / drug effects
  • Microsomes / enzymology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Mixed Function Oxygenases / metabolism
  • Sensitivity and Specificity

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ketoconazole