Effects of macrolide antibiotics on CYP3A expression in human and rat hepatocytes: Interspecies differences in response to troleandomycin

The effects of various macrolide antibiotics [triacetyloleandomycin (TAO), clarithromycin, azithromycin, roxithromycin, erythromycin base] and the new ketolide HMR3004 on CYP3A expression were evaluated in human and rat hepat ocytes. Cells were treated for 3 days with nontoxic concentrations of the d rugs, and CYP3A induction was assessed through midazolam hydroxylase activi ty and Western and Northern blot analyses. In rat hepatocytes, no induction of CYP3A1 expression was observed following exposure to macrolides, even t o erythromycin base and TAO (well known in vivo CYP3A1 inducers), whereas d examethasone and phenobarbital were confirmed to induce this enzyme. In con trast, treatment of fresh and thawed human hepatocytes with TAO, produced a n increase of midazolam hydroxylation (4-fold over control). This result wa s in agreement with the high amount of CYP3A4 protein and mRNA revealed by Western and Northern blot analyses. Other tested macrolides had no inductio n effect on CYP3A expression. These results confirmed the interspecies vari ability of CYP3A regulation in hepatocytes and raised the question of its m echanism of induction by macrolides in human liver.