Citation

Numazawa M, Yamada K. Biol. Pharm. Bull. 1999; 22(11): 1207-1211.

Copyright

(Copyright © 1999, Pharmaceutical Society of Japan)

DOI

10.1248/bpb.22.1207

PMID

10598029

Abstract

The time-dependent inactivation of aromatase by epoxy analogs of the good aromatase inhibitors, androst-4-ene-6,17-dione (3) and androst-5-ene-4,17-dione (7), 4beta,5beta-epoxy and 5beta,6beta-epoxy compounds 10 and 13 and their 19-oxo derivatives 11 and 14, was examined in either the presence or absence of NADPH. The 4beta,5beta-epoxy-19-oxo steroid 11 along with the 19-methyl-5beta,6beta-epoxide 13 inactivated human placental aromatase in a mechanism-based manner, in the presence of NADPH, with rate constants for inactivation (k(inact)) of 0.133 min(-1) for steroid 11 and 0.100 min(-1) for steroid 13, whereas the two other steroids, 10 and 14, did not. On the other hand, none of four epoxides studied caused time-dependent inactivation of aromatase in an affinity-labeling manner in the absence of NADPH. These results are the first report showing that inhibitors 11 and 13 are suicide substrates having an epoxyketone structural feature.

Language: en

Keywords

Androstenedione; Aromatase Inhibitors; Cysteine; Enzyme Inhibitors; Female; Humans; In Vitro Techniques; Kinetics; Microsomes; NADP; Placenta; Pregnancy; Stereoisomerism; Steroids; Time Factors