Selective aromatase inhibition by pyridoglutethimide, an analogue of aminoglutethimide

Abstract

The inhibitory effects of pyridoglutethimide (3-ethyl-3-(4-pyridyl)piperidine-2,6-dione), an analogue of aminoglutethimide, on aromatase and other cytochrome P-450-dependent steroid-metabolizing enzymes were studied in vitro. Pyridoglutethimide and aminoglutethimide showed competitive inhibition of human placental aromatase activity with apparent Ki values of 1.7 and 0.7 mumol/l, respectively. Both pyridoglutethimide and aminoglutethimide inhibited the aromatase activity of uterine leiomyoma and cultured choriocarcinoma Enami cells as well as immunopurified human placental aromatase cytochrome P-450 by more than 90%, with IC50 values of 10-19 and 5-7 mumol/l, respectively. These results might suggest that the inhibitors interacted directly with the aromatase cytochrome P-450 of these tissues. Aminoglutethimide inhibited bovine adrenal cholesterol side-chain cleavage activity with an IC50 value of 40 mumol/l and inhibited 21-hydroxylase activity slightly, but did not inhibit 17 alpha-, 11 beta- and 18-hydroxylase at concentrations up to 100 mumol/l. On the other hand, pyridoglutethimide had no inhibitory effect on any of these enzymes at concentrations up to 50 mumol/l, although it inhibited 11 beta- and 18-hydroxylase slightly at 100 mumol/l. These results indicated that pyridoglutethimide was an aromatase inhibitor of a comparable potency to aminoglutethimide, but that it did not inhibit other steroid hydroxylases.