Major Phase I Biotransformation Pathways of Trichostatin A in Rat Hepatocytes and in Rat and Human Liver Microsomes

Elaut, Greetje; Török, G.; Vinken, Mathieu; Laus, Gerhard; Papeleu, Peggy; Tourwé, Dirk; Rogiers, Vera

doi:10.1124/dmd.30.12.1320

Cited by 50 publications

(53 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TSA is one of the most potent HDAC inhibitors that exerts its effects at very low concentrations (nanomolar), but its poor bioavailability in vivo, due to an extensive biotransformation or instability, makes its use a continuing topic of controversy (20,(24)(25)(26). Unfortunately, none of the numerous HDAC inhibitors is specific for single isoforms of HDAC, but few drugs show preferences for groups of HDACs or for single HDACs.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Hemmatazad¹,

Rodrigues²,

Maurer³

et al. 2009

Arthritis & Rheumatism

102

View full text Add to dashboard Cite

Objective. We have recently shown a significant reduction in cytokine-induced transcription of type I collagen and fibronectin in systemic sclerosis (SSc) skin fibroblasts upon treatment with trichostatin A (TSA). Moreover, in a mouse model of fibrosis, TSA prevented the dermal accumulation of extracellular matrix. The purpose of this study was to analyze the silencing of histone deacetylase 7 (HDAC-7) as a possible mechanism by which TSA exerts its antifibrotic function.Methods. Skin fibroblasts from patients with SSc were treated with TSA and/or transforming growth factor ␤. Expression of HDACs 1-11, extracellular matrix proteins, connective tissue growth factor (CTGF), and intercellular adhesion molecule 1 (ICAM-1) was analyzed by real-time polymerase chain reaction, Western blotting, and the Sircol collagen assay. HDAC-7 was silenced using small interfering RNA.Results. SSc fibroblasts did not show a specific pattern of expression of HDACs. TSA significantly inhibited the expression of HDAC-7, whereas HDAC-3 was up-regulated. Silencing of HDAC-7 decreased the constitutive and cytokine-induced production of type I and type III collagen, but not fibronectin, as TSA had done. Most interestingly, TSA induced the expression of CTGF and ICAM-1, while silencing of HDAC-7 had no effect on their expression.Conclusion. Silencing of HDAC-7 appears to be not only as effective as TSA, but also a more specific target for the treatment of SSc, because it does not up-regulate the expression of profibrotic molecules such as ICAM-1 and CTGF. This observation may lead to the development of more specific and less toxic targeted therapies for SSc.

show abstract

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Hemmatazad¹,

Rodrigues²,

Maurer³

et al. 2009

Arthritis & Rheumatism

102

View full text Add to dashboard Cite

show abstract

“…Ten years ago, Niki and colleagues 10,11 introduced an HDI as a candidate to preserve a quiescent HSC phenotype in vitro; however, the role of individual HDACs was not addressed, because the broad spectrum inhibitor TSA was used to inhibit the in vitro HSC activation. Because of TSA's limited use in vivo 20,27 we set out to test the influence of the more selective class I HDI VPA 15,16 on the mouse model of CCl 4 -induced liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Because of TSA's limited use in vivo, 20 the influence of the HDI VPA on the mouse model of CCl 4 -induced liver fibrosis was tested because of its preference toward class I HDACs 15,21 and its documented use in mouse models. 18,22 Mice were treated with CCl 4 for 4 weeks with or without VPA in their drinking water.…”

Section: Vpa Partly Inhibits CCL 4 -Induced Fibrosismentioning

confidence: 99%

Chronic Administration of Valproic Acid Inhibits Activation of Mouse Hepatic Stellate Cells in Vitro and in Vivo

et al. 2010

View full text Add to dashboard Cite

“…Xenobiotic biotransformation is generally recognized as a key determinant of the efficacy and toxicity of a potential new drug (Li, 2001;Elaut et al, 2002). However, little information on the biotransformation of HA-based HDACi is available in the current literature, and attempts to optimize their metabolic properties have been scarce.…”

mentioning

confidence: 99%

“…However, little information on the biotransformation of HA-based HDACi is available in the current literature, and attempts to optimize their metabolic properties have been scarce. We previously showed that 50 M TSA is completely inactivated within 40 min upon incubation with rat hepatocyte suspensions (Elaut et al, 2002). Another group (Sanderson et al, 2004) subsequently reported a half-life of 6.3 min upon peritoneal administration of TSA (0.5 mg ⅐ kg) to mice.…”

mentioning

confidence: 99%

A Metabolic Screening Study of Trichostatin A (TSA) and TSA-Like Histone Deacetylase Inhibitors in Rat and Human Primary Hepatocyte Cultures

Elaut¹,

Laus²,

Alexandre³

et al. 2007

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Hydroxamic acid (HA)-based histone deacetylase (HDAC) inhibitors, with trichostatin A (TSA) as the reference compound, are potential antitumoral drugs and show promise in the creation of long-term primary cell cultures. However, their metabolic properties have barely been investigated. TSA is rapidly inactivated in rodents both in vitro and in vivo. We previously found that 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxyamide or 4-Me 2 N-BAVAH (compound 1) is metabolically more stable upon incubation with rat hepatocyte suspensions. In this study, we show that human hepatocytes also metabolize TSA more rapidly than compound 1 and that similar pathways are involved. Furthermore, structural analogs of compound 1 (compounds 2-9) are reported to have the same favorable metabolic properties. Removal of the dimethylamino substituent of compound 1 creates a very stable but 50% less potent inhibitor. Chain lengthening (4 to 5 carbon spacer) slightly improves both potency and metabolic stability, favoring HA reduction to hydrolysis. On the other hand, C␣-unsaturation and spacer methylation not only reduce HDAC inhibition but also increase the rate of metabolic inactivation approximately 2-fold, mainly through HA reduction. However, in rat hepatocyte monolayer cultures, compound 1 is shown to be extensively metabolized by phase II conjugation. In conclusion, this study suggests that simple structural modifications of amidelinked TSA analogs can improve their phase I metabolic stability in both rat and human hepatocyte suspensions. Phase II glucuronidation, however, can compensate for their lower phase I metabolism in rat hepatocyte monolayers and could play a yet unidentified role in the determination of their in vivo clearance.

show abstract

Major Phase I Biotransformation Pathways of Trichostatin A in Rat Hepatocytes and in Rat and Human Liver Microsomes

Cited by 50 publications

References 33 publications

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Chronic Administration of Valproic Acid Inhibits Activation of Mouse Hepatic Stellate Cells in Vitro and in Vivo

A Metabolic Screening Study of Trichostatin A (TSA) and TSA-Like Histone Deacetylase Inhibitors in Rat and Human Primary Hepatocyte Cultures

Contact Info

Product

Resources

About