Structure-activity relationships for gene activation oestrogenicity: evaluation of a diverse set of aromatic chemicals.
Structure-activity relationships for oestrogenicity were developed based on 120 aromatic chemicals evaluated in the Saccharomyces cerevisiae-based Lac-Z reporter assay. Relative gene activation was compared to 17 beta-estradiol and varied over eight orders of magnitude. Analysis of the data compared to 17 beta-estradiol identified three structural criteria that were related to xenoestrogen activity and potency: (1) the hydrogen-bonding ability of the phenolic ring mimicking the A-ring, (2) a hydrophobic centre similar in size and shape to the B- and C-rings, and (3) a hydrogen-bond donor mimicking the 17 beta-hydroxyl moiety of the D-ring, especially with an oxygen-to-oxygen distance similar to that between the 3- and 17 beta-hydroxyl groups of 17 beta-estradiol. Binding data were segregated into activity clusters including strong, moderate, weak, and detectable gene expression, and those compounds that were inactive. The hydrogen-bonding ability of hydroxy group in the 3-position on 17 beta-estradiol was observed to be essential for gene activation. Compounds with a 4-hydroxyl substituted benzene ring and a hydrophobic moiety of size and shape equivalent to the B-ring of 17 beta-estradiol were generally observed to be weakly active compounds. Moderately active compounds have a 4-hydroxyl substituted benzene ring with a hydrophobic moiety equivalent in size and shape to the B- and C-ring of 17 beta-estradiol, or have a high hydrogen-bond donor capacity owing to the presence of halogens on a nonphenolic ring. Strongly active compounds, similar to 4,4'-diethylethylene bisphenol (DES), possess the same hydrophobic ring structure as described for moderately active compounds and an additional hydroxyl group with an oxygen-to-oxygen distance close to that exhibited by the 3- and 17-hydroxyl groups of 17 beta-estradiol.
Schultz
T Wayne
TW
Department of Comparative Medicine, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, Tennessee 37996-4500, USA. m.t.cronin@livjm.ac.uk
Sinks
Glendon D
GD
Cronin
Mark T D
MT
D001577:Benzophenones / Q000009:adverse effects / Q000494:pharmacology; D001681:Biological Assay / Q000379:methods; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000096:biosynthesis*; D004968:Estrogens, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology; D005419:Flavonoids / Q000009:adverse effects / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006841:Hydrocarbons, Aromatic / Q000009:adverse effects* / Q000494:pharmacology; D006860:Hydrogen Bonding; D007928:Lethal Dose 50; D010636:Phenols / Q000009:adverse effects / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D001616:beta-Galactosidase / Q000096:biosynthesis
D001577:Benzophenones; D001713:Biphenyl Compounds; D004958:Estradiol; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D005419:Flavonoids; D006841:Hydrocarbons, Aromatic; D010636:Phenols; D001616:beta-Galactosidase; C010574:biphenyl