Acetylator status

A study of 484 tuberculosis patients on isoniazid showed that the development of peripheral neuropathy in a subgroup of patients was due to inherited differences in the acetylation of this medication [4], Individuals could be divided into rapid or slow acetylators of isoniazid. Family studies showed that rapid or slow acetylation status was inherited, with rapid acetylation being dominant and slow acetylation recessive. Polyneuritis was found to occur in 4 out of 5 slow acetylators, while only 2 out of 10 rapid acetylators developed polyneuritis. The rapid acetylators also tolerated longer courses of the drug [4],... 

Fig. 10.2. FSPIM analysis of the interaction between maize transcriptional coactivators—GCN5 and ADA2—fused to CFP and YFP. GCN5 is a histone acetyltransferase that, in conjunction with adaptor protein ADA2, modulates transcription in diverse eukaryotes by affecting the acetylation status of the core histones in nucleosomes [63]. CFP- and YFP-tagged proteins, expressed in protoplasts, were excited by the 458 nm and the 514 nm laser lines sequentially. CFP fluorescence was selectively detected by an FIFT 458 dichroic mirror and BP 470-500 band pass emission filter while YFP fluorescence was selectively detected by using an HFT 514 dichroic mirror and...

Figure I. Chromatin acetylation status, transcription and survival a balance between HAT and HDAC activities, (a) Transcriptional activationlrepression relies on the chromatin acetylation status of histones. TBP TATA-Binding Protein, TF Transcription Factor, TR Transcriptional Repressor, (b) A fine-tuning of HAT/HDAC activities orchestrates neuronal death and survival. On one hand, acetylation levels can be decreased (HypoAc) because of CBP loss of function, as observed during apoptosis and neurodegeneration. On the other hand, when the threshold of acetylation is exceeded (HyperAc), this ultimately leads to nemonal death. (See Colom Plate 16.)...

Chromatin Acetylation Status During Neuronal Apoptosis... 

HD In Drosophila models of Huntington s disease, the HDAC inhibitors SAHA and sodium butyrate arrest the progressive neuronal degeneration and lethality (Steffan et al, 2001). SAHA and sodium butyrate have also been demonstrated to extend survival, ameliorate motor deficits and delay characteristic neuropathology in the mouse Huntington s disease model, R6/2 (Ferrante et al, 2003 Hockly et al, 2003). In NaBu-treated animals, animals displayed enhanced acetylation status of histones and pro-survival transcription factors like Spl and reduction in several neuropatho-logical hallmarks like striatal neuronal atrophy (Ferrante et al, 2003). Consistent with the idea that HDAC inhibition relieves transcriptional repression and that protection is downstream of mutant htt, neither SAHA nor sodium butyrate decreased mutant htt expression or aggregates (Ferrante et al, 2003 Hockly et al, 2003). 

Thus, the acetylator status of a patient as determined by the NAT2 genotype appears to be an important determinant of the risk for SSZ toxicity based on the limited data published so far (see Table 14.3). Although more studies and data are clearly needed, this suggests that prospective screening of patients for the NAT2 genotype prior to initiation of SSZ may be a useful tool to prevent SSZ toxicity. 

Finally, the deacetylation of histones in methylated gene regions may be selective with respect to the histone affected. Chromatin immunoprecipitation analysis of the histone acetylation status of proviral sequences targeted to defined genome loci in MEL cells showed that the in vitro methylated proviral sequences that were transcriptionally silent in vivo, were hypoacetylated only with respect to histone H3 in contrast, the acetylation status of histone H4 was comparable on the methylated and unmethylated provirus [78]. Moreover, the H3 acetylation status correlated closely with the location of methylated CpGs along the proviral sequence. 

Collectively, the results of these studies suggest a dominant role for DNA methylation, which dictates the acetylation status of the histones, and thereby, chromatin structure (Fig. 5c). The cells jealously preserve and inherit DNA methylation patterns, and respectively chromatin conformation, through mitosis. 

Historically, histone deacetylases (HDACs) were considered as promising drug targets in anticancer therapy due to their regulating role in the histone acetylation status implicated in the epigenetic chromatin control. As a consequence, the potential of HDAC inhibitors was initially attributed to their capacity as chromatin-modulating drugs. 

The family of HDAC enzymes has been named after their first substrate identified, i.e., the nuclear histone proteins. Histone proteins (H2A, H2B, H3 and H4) form an octamer complex, around which the DNA helix is wrapped in order to establish a condensed chromatin structure. The acetylation status of histones is in a dynamic equilibrium governed by histone acetyl transferases (HATs), which acetylate and HDACs which are responsible for the deacetylation of histone tails (Fig. 1). Inhibition of the HDAC enzyme promotes the acetylation of nucleosome histone tails, favoring a more transcriptionally competent chromatin structure, which in turn leads to altered expression of genes involved in cellular processes such as cell prohferation, apoptosis and differentiation. Inhibition of HDAC activity results in the activation of only a limited set of pre-programmed genes microarray experiments have shown that 2% of all genes are activated by structmally different HDAC inhibitors [1-5]. In recent years, a growing number of additional nonhistone HDAC substrates have been identified, which will be discussed in more detail below. 

Fig.l The dynamic equilibrium between acetylation and deacetylation of lysine residues of the histones is controlled by the opposing enzymatic activities of HATs and HDACs. The acetylation status determines whether a lysine residue is either neutral (acetylated) or positively charged (deacetylated). The consequent changes in the internucleosomal interactions and condensation status of chromosomal domains govern the transcriptional competence of DNA ( Diane Bruyninckx)... 

The impact of small molecules on the acetylation status of histones has attracted the interest of the medicinal chemistry community for almost a decade now. Nevertheless, the fast and reversible increase in cellular histone acetylation in the presence of -butyrate was already recognized in 1977 by Riggs et al. (Fig. 3) [30]. Two years later, it was proven that n-butyrate, among some related and less active small linear aliphatic carboxylates, was a noncompetitive inhibitor of histone deacetylating enzymes [31-34]. More than ten years after the initial interest in -butyrate, Yoshida et al. showed that trichostatin A (TSA, Fig. 3), originally reported as an antifungal agent [35],... 

Mefabo//sm - The half-life of INH is widely variable and dependent on acetylator status. Isoniazid is primarily acetylated by the liver this process is genetically controlled. Fast acetylators metabolize the drug about 5 to 6 times faster than slow acetylators. Several minor metabolites have been identified, one or more of which may be reactive (monoacetylhydrazine is suspected), and responsible for liver damage. The rate of acetylation does not significantly alter the effectiveness of INH. However, slow acetylation may lead to higher blood levels of the drug, and thus to an increase in toxic reactions. 

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