Differential effects of hydroxamate histone deacetylase inhibitors on cellular functionality and gap junctions in primary cultures of mitogen-stimulated hepatocytes.
Histone deacetylase (HDAC)-inhibitors are well known to induce proliferative blocks and concomitant differentiation boosts in a plethora of tumor cells. Despite their promising potential as clinical therapeutics, however, the biological outcome of HDAC-inhibitors in non-tumorous cells has been poorly documented. We previously reported that the HDAC-inhibitor trichostatin A (TSA) and its metabolically more stable structural analogue 5-(4-dimethylaminobenzoyl)-aminovaleric acid hydroxamide (4-Me2N-BAVAH) cause cell cycle arrests in primary cultures of mitogen-stimulated hepatocytes. The present study was set up to explore whether this proliferative block in non-tumorous cells is also associated with inducing effects on the differentiated hepatocellular phenotype, a scenario that is usually observed in tumorous cells. In particular, the molecular actions of TSA and 4-Me2N-BAVAH on hepatic functionality and gap junctions, gatekeepers of liver homeostasis, in primary cultures of mitogen-stimulated hepatocytes are investigated. Both HDAC-inhibitors were found to promote albumin secretion and CYP1A1 gene transcription and functionality, whereas CYP2B1 gene transcription and activity were only slightly enhanced. The protein production of the gap junction component Cx26 was downregulated, whereas Cx32 expression was upregulated in response to HDAC-inhibition. Furthermore, TSA increased protein levels of the non-specific hepatocellular Cx43, whereas 4-Me2N-BAVAH rather diminished its expression. These data provide new insight into the biological impact of HDAC-inhibitors on the homeostatic balance in hepatocytes, being major executors of xenobiotic biotransformation and primary targets of drug-induced toxicity.
Henkens
Tom
T
Department of Toxicology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium. Tom.Henkens@vub.ac.be
Vinken
Mathieu
M
Lukaszuk
Aneta
A
Tourwé
Dirk
D
Vanhaecke
Tamara
T
Rogiers
Vera
V
D000107:Acetylation / Q000187:drug effects; D000418:Albumins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000072259:Connexin 26; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D010421:Pentanoic Acids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000097002:Gap Junction beta-1 Protein
D000418:Albumins; D000072259:Connexin 26; D018031:Connexin 43; D017630:Connexins; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D004815:Epidermal Growth Factor; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D008934:Mitogens; D010421:Pentanoic Acids; D000097002:Gap Junction beta-1 Protein; C521334:5-(4-dimethylaminobenzoyl)-aminovaleric acid hydroxamate; C000607044:Gjb2 protein, rat; C012589:trichostatin A