Structure-activity relationships of phthalates in inhibition of human placental 3β-hydroxysteroid dehydrogenase 1 and aromatase

Reprod Toxicol. 2016 Jun:61:151-61. doi: 10.1016/j.reprotox.2016.04.004. Epub 2016 Apr 8.

Abstract

Phthalates are associated with preterm delivery. However, the mechanism is unclear. Progesterone formed by 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) and estradiol by aromatase (CYP19A1) in placenta are critical for maintaining pregnancy. In this study, we compared structure-activity relationships (SAR) of 14 phthalates varied in carbon atoms in alcohol moiety to inhibit human HSD3B1 in COS1 and CYP19A1 in JEG-3 cells. There were responses in that only diphthalates with 4-7 carbon atoms were competitive HSD3B1 inhibitors and diphthalates with 6 carbon atoms were CYP19A1 inhibitors. IC50s of dipentyl (DPP), bis(2-butoxyethyl) (BBOP), dicyclohexyl (DCHP), dibutyl (DBP), and diheptyl phthalate (DHP) were 50.12, 32.41, 31.42, 9.69, and 4.87μM for HSD3B1, respectively. DCHP and BBOP inhibited CYP19A1, with IC50s of 64.70 and 56.47μM. DPP, BBOP, DCHP, DBP, and DHP inhibited progesterone production in JEG-3 cells. In conclusion, our results indicate that there is clear SAR for phthalates in inhibition of HSD3B1 and CYP19A1.

Keywords: -hydroxysteroid dehydrogenase 1; 3β Aromatase; Competitive inhibition; Progesterone; Steroids.

MeSH terms

  • Animals
  • Aromatase / metabolism*
  • Aromatase Inhibitors* / chemistry
  • Aromatase Inhibitors* / pharmacology
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Environmental Pollutants* / chemistry
  • Environmental Pollutants* / pharmacology
  • Estradiol / metabolism
  • Humans
  • Microsomes / metabolism
  • Mitochondria / metabolism
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / metabolism
  • Phthalic Acids* / chemistry
  • Phthalic Acids* / pharmacology
  • Progesterone / metabolism
  • Progesterone Reductase / antagonists & inhibitors*
  • Progesterone Reductase / metabolism
  • Steroid Isomerases / antagonists & inhibitors*
  • Steroid Isomerases / metabolism
  • Structure-Activity Relationship

Substances

  • 3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase
  • Aromatase Inhibitors
  • Environmental Pollutants
  • Multienzyme Complexes
  • Phthalic Acids
  • Progesterone
  • Estradiol
  • Progesterone Reductase
  • Aromatase
  • CYP19A1 protein, human
  • Steroid Isomerases