Hydralazine and related compounds: Chemistry, metabolism, and mode of action

Reece, Phillip A.

doi:10.1002/med.2610010105

Cited by 69 publications

(33 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This property seemed to reflect hydralazine's ability to efficiently scavenge free acrolein in buffered solutions (Burcham et al, 2003b). Such actions are consistent with the chemical properties of hydralazine, which, as a strong nucleophile, readily forms hydrazones with several biogenic keto compounds (Reece, 1981). Indeed, we recently isolated two novel hydrazones formed during reactions between acrolein and hydralazine (L. M. Kaminskas, P. C. Burcham, and S. M. Pyke, manuscript in preparation).…”

supporting

confidence: 58%

Strong Protein Adduct Trapping Accompanies Abolition of Acrolein-Mediated Hepatotoxicity by Hydralazine in Mice

Kaminskas

Pyke²,

Burcham³

2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Acrolein is a highly reactive ␣,␤-unsaturated aldehyde that readily alkylates nucleophilic centers in cell macromolecules. Typically, such reactions proceed via Michael addition chemistry, forming adducts that retain an electrophilic carbonyl group. Since these species participate in secondary deleterious reactions, we hypothesize that inactivation of carbonyl adducts may attenuate acrolein toxicity. Indeed, we recently established that the nucleophilic antihypertensive drug hydralazine readily "traps" acrolein adducts in cell proteins and strongly suppresses acrolein-mediated toxicity in isolated hepatocytes. This work sought to determine whether hydralazine prevents the in vivo hepatotoxicity of the acrolein precursor allyl alcohol in whole mice and whether adduct trapping accompanies any such hepatoprotection. Mice received allyl alcohol alone or in conjunction with several doses of hydralazine. Four hours later, mice were sacrificed to allow for the determination of liver enzymes in plasma as markers of hepatic injury, whereas livers were assessed for glutathione and hydralazine-stabilized protein adducts. Hydralazine afforded strong, dose-dependent protection against the increases in plasma marker enzymes but not the hepatic glutathione depletion produced by allyl alcohol. Western blotting revealed intense, dose-dependent adduct trapping by hydralazine in numerous liver proteins over a broad 26-to 200-kDA mass range. In keeping with these findings, immunohistochemical analysis of liver slices indicated diffuse, extranuclear adduct trapping by hydralazine that was uniformly distributed across the liver lobule, with partial localization in parenchymal cell membranes. These findings concur with our hypothesis that hydralazine readily inactivates reactive carbonyl-retaining protein adducts formed by acrolein, thereby preventing secondary reactions that trigger cellular death.

show abstract

supporting

confidence: 58%

Strong Protein Adduct Trapping Accompanies Abolition of Acrolein-Mediated Hepatotoxicity by Hydralazine in Mice

Kaminskas

Pyke²,

Burcham³

2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…In pharmacological terms, hydralazine is a vasodilatory antihypertensive agent, but its ability to suppress acrolein toxicity is more likely caused by its chemical properties. Possessing a strongly nucleophilic hydrazine, it readily scavenges several biogenic keto compounds; e.g., formation of a pyruvic hydrazone is a key systemic fate in humans (Reece, 1981). We have recently isolated two novel hydrazones formed during acrolein scavenging by hydralazine (L. M. Kaminskas, S. M. Pyke, and P. C. Burcham, unpublished observations).…”

mentioning

confidence: 99%

Protein Adduct-Trapping by Hydrazinophthalazine Drugs: Mechanisms of Cytoprotection Against Acrolein-Mediated Toxicity

Burcham¹,

Fontaine²,

Kaminskas³

et al. 2004

Molecular Pharmacology

View full text Add to dashboard Cite

Acrolein is a highly toxic aldehyde involved in a number of diseases as well as drug-induced toxicities. Its pronounced toxicity reflects the readiness with which it forms adducts in proteins and DNA. As a bifunctional electrophile, initial reactions between acrolein and protein generate adducts containing an electrophilic center that can participate in secondary deleterious reactions (e.g., cross-linking). We hypothesize that inactivation of these reactive protein adducts with nucleophilic drugs may counteract acrolein toxicity. Because we previously observed that 1-hydrazinophthalazine (hydralazine) strongly diminishes the toxicity of the acrolein precursor allyl alcohol, we explored the possibility that hydralazine targets reactive acrolein adducts in proteins. We report that hydralazine abolished the immunoreactivity of an acrolein-modified model protein (bovine serum albumin), but only if the drug was added to the protein within 30 min of commencing modification by acrolein. The ability of a range of carbonyl-trapping drugs to interfere with "early" events in protein modification strongly correlated with their protective potencies against allyl alcohol toxicity in hepatocytes. In mass spectrometry studies using a model lysine-containing peptide, hydralazine rapidly formed hydrazones with Michael adducts generated by acrolein. Using an antibody raised against such ternary drug-acroleinprotein complexes in Western blotting experiments, clear adduct-trapping was evident in acrolein-preloaded hepatocytes exposed to cytoprotective concentrations of hydralazine ranging from 2 to 50 M. These novel findings begin to reveal the molecular mechanisms whereby hydralazine functions as an efficient "protein adduct-trapping" drug.

show abstract

“…Using hydralazine, an antihypertensive agent long known to trap biogenic carbonyl compounds (Reece, 1981), we found that the molecular chaperone Hsp90 is mobilized to subcellular locations containing damaged proteins. A key participant during the triage of abnormal, unfolded proteins, Hsp90 helps cells withstand a range of proteotoxic stresses (Taipale et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Among the strongest nucleophiles in clinical use, the antihypertensive hydralazine efficiently traps numerous carbonyl compounds within the plasma of human recipients (Reece, 1981). Under test-tube or cell-free conditions, hydralazine displays pronounced reactivity toward acrolein (Kaminskas et al, 2004a).…”

Section: Introductionmentioning

confidence: 99%

Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

Burcham

Raso²,

Kaminskas

2012

Mol Pharmacol

View full text Add to dashboard Cite

Toxic carbonyls such as acrolein participate in many degenerative diseases. Although the nucleophilic vasodilatory drug hydralazine readily traps such species under "test-tube" conditions, whether these reactions adequately explain its efficacy in animal models of carbonyl-mediated disease is uncertain. We have previously shown that hydralazine attacks carbonyl-adducted proteins in an "adduct-trapping" reaction that appears to take precedence over direct "carbonyl-sequestering" reactions, but how this reaction conferred cytoprotection was unclear. This study explored the possibility that by increasing the bulkiness of acrolein-adducted proteins, adduct-trapping might alter the redistribution of chaperones to damaged cytoskeletal proteins that are known targets for acrolein. Using A549 lung adenocarcinoma cells, the levels of chaperones heat shock protein (Hsp) 40, Hsp70, Hsp90, and Hsp110 were measured in intermediate filament extracts prepared after a 3-h exposure to acrolein. Exposure to acrolein alone modestly increased the levels of all four chaperones. Coexposure to hydralazine (10 -100 M) strongly suppressed cell ATP loss while producing strong adduct-trapping in intermediate filaments. Most strikingly, hydralazine selectively boosted the levels of cytoskeletal-associated Hsp90, including a high-mass species that was sensitive to the Hsp90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin. Biochemical fractionation of acrolein-and hydralazine-treated cells revealed that hydralazine likely promoted Hsp90 migration from cytosol into other subcellular compartments. A role for Hsp90 mobilization in cytoprotection was confirmed by the finding that brief heat shock treatment suppressed acute acrolein toxicity in A549 cells. Taken together, these findings suggest that by increasing the steric bulk of carbonyl-adducted proteins, adduct-trapping drugs trigger the intracellular mobilization of the key molecular chaperone Hsp90.

show abstract

Hydralazine and related compounds: Chemistry, metabolism, and mode of action

Cited by 69 publications

References 67 publications

Strong Protein Adduct Trapping Accompanies Abolition of Acrolein-Mediated Hepatotoxicity by Hydralazine in Mice

Strong Protein Adduct Trapping Accompanies Abolition of Acrolein-Mediated Hepatotoxicity by Hydralazine in Mice

Protein Adduct-Trapping by Hydrazinophthalazine Drugs: Mechanisms of Cytoprotection Against Acrolein-Mediated Toxicity

Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

Contact Info

Product

Resources

About