Abstract
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 hepatocytes. Cells were treated for 3 days with nontoxic concentrations of the drugs, and CYP3A induction was assessed through midazolam hydroxylase activity and Western and Northern blot analyses. In rat hepatocytes, no induction of CYP3A1 expression was observed following exposure to macrolides, even to erythromycin base and TAO (well known in vivo CYP3A1 inducers), whereas dexamethasone and phenobarbital were confirmed to induce this enzyme. In contrast, treatment of fresh and thawed human hepatocytes with TAO, produced an increase of midazolam hydroxylation (4-fold over control). This result was in agreement with the high amount of CYP3A4 protein and mRNA revealed by Western and Northern blot analyses. Other tested macrolides had no induction effect on CYP3A expression. These results confirmed the interspecies variability of CYP3A regulation in hepatocytes and raised the question of its mechanism of induction by macrolides in human liver.
Footnotes
-
Send reprint requests to: Dr. Rahmani, Laboratoire de Pharmacotoxicologie, INRA, 41 bd du Cap, 06606 Antibes, France. E-mail:rahmani{at}antibes.inra.fr
-
This work was supported by the Department of Pharmacotoxicology of Hoechst Marion Roussel and has been presented in part at the 12th International Symposium on Microsomes and Drug Oxidation, 1998 (Montpellier, France).
- Abbreviations used are::
- TAO
- triacyloleandomycin
- ERY
- erythromycin base
- CLA
- clarithromycin
- ROX
- roxitromycin
- AZI
- azithromycin
- CYP
- cytochrome P-450
- DEX
- dexamethasone
- MDZ
- midazolam
- 3-MC
- 3-methylcholanthrene
- PB
- phenobarbital
- RIF
- rifampicin
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- PCR
- polymerase chain reaction
- Received December 22, 1999.
- Accepted September 13, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|