Histone deacetylase inhibitors and a functional potent inhibitory effect on human uterine contractility.
OBJECTIVE
This study was undertaken to investigate the effects of 3 histone deacetylase inhibitors on human uterine contractility.


METHODS
Biopsy specimens of human myometrium were obtained at elective cesarean section (n = 18). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous, and oxytocin-induced contractions, were subjected to cumulative additions of 3 histone deacetylase inhibitors: trichostatin A, suberic bishydroxamate (1 nmol/L-10 micromol/L) and valproic acid (100 nmol/L--1 mmol/L). Control experiments were run simultaneously. Integrals of contractile activity were measured by using the PowerLab hardware unit and Chart v3.6 software. Data were analyzed by using 1-way analysis of variance, followed by post hoc analysis.


RESULTS
All 3 histone deacetylase inhibitor compounds exerted a potent and cumulative inhibitory effect on spontaneous (n = 18) and oxytocin-induced (n =18) contractility. The mean maximal inhibition values for the 3 compounds were as follows: trichostatin A, 46-54% (P < .05); valproic acid, 35-36% (P < .05); and suberic bishydroxamate, 53-65% (P < .05).


CONCLUSIONS
The histone deacetylase inhibitors trichostatin A, valproic acid, and suberic bishydroxamate exerted a potent inhibitory effect on human uterine contractions. This raises the possibility that this new class of compounds may have tocolytic potential, in addition to their current clinical indications. We speculate that this inhibitory effect may be linked, at least in part, to the ability of histone deacetylase inhibitors to induce the expression of genes involved in maintaining myometrial quiescence via epigenetic mechanisms but may also potentially involve nonepigenetic pathways.
Moynihan
Audrey T
AT
Department of Obstetrics and Gynaecology, Clinical Science Institute, University College Hospital Galway, Galway, Ireland.
Hehir
Mark P
MP
Sharkey
Aidan M
AM
Robson
Stephen C
SC
Europe-Finner
G Nicholas
GN
Morrison
John J
JJ
D000328:Adult; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D010120:Oxytocics / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D011247:Pregnancy; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010120:Oxytocics; D011500:Protein Synthesis Inhibitors; C493163:suberic bishydroxamate; C012589:trichostatin A; D010121:Oxytocin; D014635:Valproic Acid