Endocrine disruptors that disrupt the transcription mediated by androgen receptor

Abstract

The Ministry of Environment in Japan (formerly the Japan Environment Agency) has made a priority list of compounds, SPEED 98, to preferentially examine whether they act as endocrine active chemicals and conducted a project to scientifically address endocrine disruptor issues. Out of around 100 compounds listed in SPEED 98 and related compounds, thirty-six acted as pure androgen receptor (AR) antagonists, whereas 13 showed both AR agonist and antagonist activities based on an in vitro reporter gene assay. The structural difference between AR agonists and antagonists was explained by Comparative Molecular Field Analysis (CoMFA). The precise structural requirements for AR agonists and/or antagonists are described as follows: in the case of AR agonist, the distance between two functional groups with H-bonding ability corresponding to 3-keto and 17β-OH groups should be near 10 A to maintain a favorable H-bond position while the length axis of antagonists should be less than or more than 10 A so as not to make an H-bond by interaction with Asn705 and Thr877 in the steroid D ring anchoring pocket, preventing the correct positioning of helix 3 (H3) and helix 12 (H12). This hypothetical general rule is named Near 10 A polar Interaction Rule.