Aromatase inhibition: determinants of response and resistance

INTRODUCTION The biosynthesis of natural oestrogens involves a series of steroid transformations, as depicted in Figure 1. Blockade of any conversion in the pathway will potentially decrease oestrogen production but the most specific effect results from inhibition of the final step in the sequence which is unique to oestrogen biosynthesis. This reaction involves the conversion of C19 androgens into C18 oestrogens with the concomitant aromatisation of the steroid A ring: because of the latter the enzyme complex performing the conversion is termed aromatase. The transformation involves 3 hydroxylations, using NADPH as a cofactor and a specific cytochrome p450 as prosthetic group within the enzyme. The key role of aromatase in oestrogen biosynthesis has led to the development of inhibitors of the enzyme which may be divided into two major subtypes: type I which compete for androgen substrate at the catalytic site of the enzyme, and type II which