Endocrine Abstracts

Statins are drugs used for the treatment of hypercholesterolemia. Statins have two chiral centers in their molecules, thus they form four enantiomers (3R5R-, 3R5S-, 3S5R- and 3S5S-). Regarding the most frequently prescribed statins, following enantiopure formulations are used in the clinics: 3R5R-atorvastatin, 3R5S-rosuvastatin and 3R5S-fluvastatin. Individual enantiomers of one drug can qualitatively and quantitatively differ in their biological activities. In some cases, only one enantiomer is responsible for the therapeutic effect, while the opposite one may be inactive or can cause undesired or even toxic effects. Therefore, it is of value to study in vitro effects of individual enantiomers.

We investigated enantiospecific interactions of four enantiopure forms of atorvastin, rosuvastatin and fluvastatin with main transcriptional regulators of drug-metabolizing enzymes - aryl hydrocarbon receptor (AhR), glucocorticoid receptor (GR) and pregnane X receptor (PXR). Agonist and antagonist activities of tested compounds towards AhR, PXR and GR were determined using human reporter cell lines. Moreover, we have measured expression of drug-metabolizing enzymes CYPs on mRNA and protein level in primary human hepatocytes.

Basal and ligand-inducible transcriptional activity of PXR was dose-dependently influenced by all tested statins, and the potency and efficacy between individual optical isomers varied depending on statin and optical isomer. Statins did not influence the expression of CYP1A1/2 in human hepatocytes. All statins induced CYP2A6, CYP2B6 and CYP3A4, and the effects on CYP2C9 were rather modulatory. Overall, the potential for drug-drug interactions involving induction of P450s was higher for clinically used optical isomers of rosuvastatin, atorvastatin and fluvastatin, as compared to their respective enantiomers, which are not in therapeutic use.