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

1. Troglitazone was the first thiazolidinedione approved for clinical use i n the treatment of non-insulin-dependent diabetes mellitus. During clinical investigations of drug-drug interactions with therapeutics (terfenadine an d cyclosporine) known to be metabolized by CYP3A4, pharmacokinetic interact ions were noted upon troglitazone multiple-dose treatments. The nature of t he interactions suggested induction of CYP3A enzymes. 2. Primary cultures of human hepatocytes were used to investigate the induc tion potential of troglitazone with respect to CYP3A4, CYP2B6 and CYP1A1/2. In human hepatocytes, troglitazone induced both immunoreactive CYP3A4 prot ein and testosterone OP-hydroxylase activity in a dose-dependent fashion (E C50 = 5-10 mu M), accompanied by an increase in CYP3A4 mRNA. The capacity o f troglitazone to induce CYP3A4 was between that of rifampin (EC50 = simila r to 0.8 mu M) and dexamethasone (40-50 mu M). Troglitazone increased CYP2B 6 immunoreactive: protein but did not significantly effect CYP1A1/2 activit y, immunoreactive protein or mRNA. 3. Troglitazone produced significant increases in CYP3A message, protein an d activity in primary rat hepatocytes, a slight increase in CYP2B1/2 activi ty and no change in CYP1A1/2 message or activity. 4. These results provide evidence that troglitazone can induce CYP3A and CY P2B enzymes while apparently not altering CYP1A. This provides a rationale for the clinically observed interactions of troglitazone with selected CYP3 A4 substrates.