Effect of troglitazone on cytochrome P450 enzymes in primary cultures of human and rat hepatocytes

Xenobiotica. 2000 Mar;30(3):273-84. doi: 10.1080/004982500237668.


1. Troglitazone was the first thiazolidinedione approved for clinical use in the treatment of non-insulin-dependent diabetes mellitus. During clinical investigations of drug-drug interactions with therapeutics (terfenadine and cyclosporine) known to be metabolized by CYP3A4, pharmacokinetic interactions were noted upon troglitazone multiple-dose treatments. The nature of the interactions suggested induction of CYP3A enzymes. 2. Primary cultures of human hepatocytes were used to investigate the induction potential of troglitazone with respect to CYP3A4, CYP2B6 and CYP1A1/2. In human hepatocytes, troglitazone induced both immunoreactive CYP3A4 protein and testosterone 6beta-hydroxylase activity in a dose-dependent fashion (EC50 = 5-10 microM), accompanied by an increase in CYP3A4 mRNA. The capacity of troglitazone to induce CYP3A4 was between that of rifampin (EC50 = 0.8 microM) and dexamethasone (40-50 microM). Troglitazone increased CYP2B6 immunoreactive protein but did not significantly effect CYP1A1/2 activity, immunoreactive protein or mRNA. 3. Troglitazone produced significant increases in CYP3A message, protein and activity in primary rat hepatocytes, a slight increase in CYP2B1/2 activity and no change in CYP1A1/2 message or activity. 4. These results provide evidence that troglitazone can induce CYP3A and CYP2B enzymes while apparently not altering CYP1A. This provides a rationale for the clinically observed interactions of troglitazone with selected CYP3A4 substrates.

Publication types

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

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Blotting, Western
  • Cells, Cultured
  • Chromans / pharmacology*
  • Cytochrome P-450 CYP1A1 / metabolism
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dexamethasone / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Glucocorticoids / pharmacology
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Liver / drug effects*
  • Male
  • Microsomes, Liver / metabolism
  • Mixed Function Oxygenases / metabolism
  • Oxidoreductases, N-Demethylating / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rifampin / pharmacology
  • Steroid Hydroxylases / metabolism
  • Substrate Specificity
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Troglitazone


  • Chromans
  • Enzyme Inhibitors
  • Glucocorticoids
  • Hypoglycemic Agents
  • RNA, Messenger
  • Thiazoles
  • Thiazolidinediones
  • Dexamethasone
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • steroid hormone 6-beta-hydroxylase
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating
  • Troglitazone
  • Rifampin