Role of methoxyestradiols in the growth inhibitory effects of estradiol on human glomerular mesangial cells.
Metabolism of locally applied 17beta-estradiol (estradiol) to methoxyestradiols contributes to the growth inhibiting effects of estradiol on vascular smooth muscle cells via an estrogen receptor (ER)-independent mechanism. Because vascular smooth muscle cells are phenotypically similar to glomerular mesangial cells, it is feasible that estradiol inhibits glomerular mesangial cell growth via a similar mechanism, and this possibility was investigated. In human glomerular mesangail cells, estradiol concentration dependently (1 to 100 nmol/L) inhibited serum-induced proliferation (cell number) and DNA ((3)[H]-thymidine incorporation) and collagen ((3)[H]-proline incorporation) synthesis. The inhibitory effects of estradiol were mimicked by 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of estradiol with little affinity for ERs. 2-Hydroxyestradiol and 2-methoxyestradiol were more potent growth inhibitors than estradiol. The inhibitory effects of estradiol were enhanced by CYP450 inducers 3-methylcholanthrene (10 micromol/L) and phenobarbital (10 micromol/L) and blocked by the CYP450 inhibitor 1-aminobenzotriazole (10 micromol/L). The growth inhibitory effects of estradiol were also blocked by quercetin (10 micromol/L) and OR 486 (10 micromol/L) inhibitors of catechol-O-methyltransferase (converts catecholestradiols to methoxyestradiols). ICI182780 (ER antagonist with ER binding affinity similar to estradiol) blocked the growth inhibitory effects of estradiol (1 to 100 nmol/L) only at concentrations (>50 micromol/L) that inhibited estradiol metabolism to catecholestradiols. The growth inhibitory effects of 2-hydroxyestradiol were abrogated by quercetin and OR486 (two structurally dissimilar catechol-O-methyltransferase inhibitors), but not by ICI182780. However, the growth inhibitory effects of 2-methoxyestradiol were unaltered by catechol-O-methyltransferase inhibitors and ICI182780. In conclusion, our findings provide the first evidence that methoxyestradiols mediate the growth inhibitory effects of locally applied estradiol on glomerular mesangial cell growth via an ER-independent mechanism.
Dubey
Raghvendra K
RK
Department of Obstetrics and Gynecology, University Hospital Zurich, Switzerland. rag@fhk.usz.ch
Gillespie
Delbert G
DG
Keller
Paul J
PJ
Imthurn
Bruno
B
Zacharia
Lefteris C
LC
Jackson
Edwin K
EK
D065098:Catechol O-Methyltransferase Inhibitors; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D006801:Humans
D065098:Catechol O-Methyltransferase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D004958:Estradiol