Trichostatin A-like hydroxamate histone deacetylase inhibitors as therapeutic agents: toxicological point of view

Abstract

Modulation of chromatin structure through histone acetylation/deacetylation is known to be one of the major mechanisms involved in the regulation of gene expression. Two opposing enzyme activities determine the acetylation state of histones: histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively acetylating or deacetylating the epsilon-amino groups of lysine residues located in the amino-terminal tails of the histones. In general, transcriptionally active chromatin is associated with hyperacetylated histones, whilst silenced chromatin is linked to hypoacetylated histones. A number of structurally divergent classes of HDAC inhibitors have been identified. They have been shown to induce cell cycle arrest, terminal differentiation and/or apoptosis in various cancer cell lines and inhibit tumor growth in animals. In particular, the reversible HDAC inhibitor Trichostatin A (TSA) and its hydroxamate analogues can effectively and selectively induce tumor growth arrest at very low concentrations (nano- to micromolar range). They form a group of so-called promising antitumor agents of which some are currently under clinical trial. Since the selection of a molecule for further drug development requires a balance of biological potency, safety and pharmacokinetics, it is of paramount importance to elucidate the pharmacokinetic and toxicological properties of these HDAC inhibitors before they can be considered as potential new drugs. Primary hepatocytes and their cultures are well-differentiated in vitro models and can be used to study simultaneously the biological effects of HDAC inhibitors and their biotransformation. The present review provides a state-of-the-art of our current knowledge of the pharmacological and toxicological effects on proliferating cells of TSA and its hydroxamate-based structural analogues. Besides a theoretical basis, an overview of the experimental results, obtained by the authors using primary rat hepatocytes as an in vitro model, is given.