A MOLECULAR-MODEL FOR THE INTERACTION BETWEEN VOROZOLE AND OTHER NONSTEROIDAL INHIBITORS AND HUMAN CYTOCHROME-P450 19 (P450 AROMATASE)

In a previous study (Vanden Bossche et al., Breast Cancer Res. Treat. 30 (1994) 43) the interaction between (+)-S-vorozole and the I-helix o f cytochrome P450 19 (P450 aromatase) has been reported. In the presen t study we extended the ''I-helix model'' by incorporating the C-termi nus of P450 aromatase. The crystal structures of P450 101 (P450 cam), 102 (P450 BM-3) and 108 (P450 terp) reveal that the C-terminus is stru cturally conserved and forms part of their respective substrate bindin g pocket. Furthermore, the present study is extended to the interactio n between P450 aromatase and its natural substrate androstenedione and the non-steroidal inhibitors (-)-R-vorozole, (-)-S-fadrozole, R-liaro zole and (-)-R-aminoglutethimide. It is found that (+)-S-vorozole, (-) -S -fadrozole and R-liarozole bind in a comparable way to P450 aromata se and interact with both the I-helix (Glu(302) and Asp(309)) and C-te rminus (Ser(478) and His(480)). The weak activity of (-)-R-aminoglutet himide might be attributed to a lack of interaction with the C-terminu s.