title: Structure-activity relationships of phthalates in inhibition of human placental 3β-hydroxysteroid dehydrogenase 1 and aromatase.
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.
authors.affiliation: Department of Pharmacy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors.forename: Ren-Ai
authors.initials: RA
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors.forename: Baiping
authors.initials: B
authors.lastname: Mao
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors.forename: Senlin
authors.initials: S
authors.lastname: Li
authors.affiliation: Center of Scientific Research, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Li
authors.affiliation: Center of Scientific Research, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors.forename: Huitao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors.forename: Qing-Quan
authors.initials: QQ
authors.lastname: Lian
authors.affiliation: Department of Pharmacy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China. Electronic address: r_ge@yahoo.com.
authors.forename: Ren-Shan
authors.initials: RS
authors.lastname: Ge
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004785:Environmental Pollutants / Q000737:chemistry / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010795:Phthalic Acids / Q000737:chemistry / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism; D011375:Progesterone Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D047072:Aromatase Inhibitors; D004785:Environmental Pollutants; D009097:Multienzyme Complexes; D010795:Phthalic Acids; D011374:Progesterone; D004958:Estradiol; D011375:Progesterone Reductase; D001141:Aromatase; C561410:CYP19A1 protein, human; D013251:Steroid Isomerases
keywords: -hydroxysteroid dehydrogenase 1; 3&beta; Aromatase; Competitive inhibition; Progesterone; Steroids