Hydralazine as an inhibitor of lysyl oxidase activity

Numata, Yukiko; Takei, T.; Hayakawa, Taro

doi:10.1016/0006-2952(81)90505-0

Cited by 14 publications

(5 citation statements)

References 10 publications

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“…2, the covalent binding of [ 14 C]rofecoxib to aortic homogenate in vitro was significantly decreased by pretreatment of the homogenate with D-penicillamine or hydralazine, which has been reported to react with protein aldehydes in connective tissues and to form a thiazolidine or hydrazone analog (hydralazine is also able to inhibit LOX activity) (Pinnell et al, 1968;Deshmukh and Nimni, 1969;Gallop and Paz, 1975;Numata et al, 1981;Howard-Lock et al, 1986). BAPN, a specific inhibitor of LOX (Tang et al, 1983), also significantly decreased the binding, probably via the prevention of allysine production from lysine or by the reduction of a number of aldehyde groups of allysine by reacting chemically with aldehyde groups through Schiff's base formation.…”

Section: Discussionmentioning

confidence: 99%

Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Oitate¹,

Hirota²,

Takahashi³

et al. 2006

J Pharmacol Exp Ther

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We have previously reported that oral administration of [14 C]rofecoxib to rats resulted in the long retention of radioactivity by the aorta as a consequence of covalent binding to elastin. Treatment of rats with ␣-phenyl-␣-propylbenzeneacetic acid 2-[diethylamino]-ethyl ester hydrochloride (SKF-525A), a cytochrome P450 inhibitor, significantly decreased the systemic exposure of 5-hydroxyrofecoxib, one of the main metabolites of rofecoxib, whereas there was no statistically significant change in the retention of radioactivity from [14 C]rofecoxib in the aorta. On the other hand, the aortic retention of radioactivity closely correlated to the systemic exposure of unchanged rofecoxib in the dose range between 2 and 10 mg/kg. A covalent binding study of [14 C]rofecoxib in vitro using rat aorta homogenate in the presence of D-penicillamine, hydralazine, ␤-aminopropionitrile, and sodium borohydride suggested that the aldehyde group of allysine in elastin was relevant to the covalent binding. In a model reaction using benzaldehyde, rofecoxib but not 5-hydroxyrofecoxib reacted with the aldehyde group of benzaldehyde in a manner of condensation reaction under a physiological pH condition. A histopathological examination using an electron microscope demonstrated that multiple oral administration of rofecoxib to rats caused marked degradation of the elastic fiber system of the aorta. These results suggested that rofecoxib as such is reactive in vivo, undergoing a condensation reaction with allysine, thereby preventing the formation of cross-linkages in elastin, i.e., desmosine and isodesmosine, and causing the degradation of the elastic fibers.

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Section: Discussionmentioning

confidence: 99%

Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Oitate¹,

Hirota²,

Takahashi³

et al. 2006

J Pharmacol Exp Ther

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“…It has been well established that small-molecule aryl hydrazines, especially phenylhydrazine 1 , can act as irreversible inhibitors for LOX and most other quinone-containing amine oxidases 20–23 . Indeed, LOX's LTQ cofactor was originally identified by mass spectrometry and Edman degradation analysis of the adduct formed between LOX and 14 C-phenylhydrazine 24 .…”

Section: Introductionmentioning

confidence: 99%

Comparing hydrazine-derived reactive groups as inhibitors of quinone-dependent amine oxidases

Burke

Severson

Mool

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Lysyl oxidase has emerged as an important enzyme in cancer metastasis. Its activity has been reported to become upregulated in several types of cancer, and blocking its activity has been shown to limit the metastatic potential of various cancers. The small-molecules phenylhydrazine and β-aminopropionitrile are known to inhibit lysyl oxidase; however, issues of stability, toxicity, and poorly defined mechanisms limit their potential use in medical applications. The experiments presented herein evaluate three other families of hydrazine-derived compounds – hydrazides, alkyl hydrazines, and semicarbazides – as irreversible inhibitors of lysyl oxidase including determining the kinetic parameters and comparing the inhibition selectivities for lysyl oxidase against the topaquinone-containing diamine oxidase from lentil seedlings. The results suggest that the hydrazide group may be a useful core functionality that can be developed into potent and selective inhibitors of lysyl oxidase and eventually find application in cancer metastasis research.

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“…Pretreatment of BAPN, a specific inhibitor of LOX (Tang et al, 1983), significantly decreased the covalent binding of [ 14 C]rofecoxib, probably via the prevention of allysine production from lysine. The covalent binding of [ 14 C]rofecoxib was also significantly decreased by pretreatment with D-penicillamine and hydralazine, which have been reported to react with protein aldehydes in connective tissues and to form thiazolidine or hydrazone analog (hydralazine can also inhibit LOX activity) Deshmukh and Nimni, 1969;Gallop and Paz, 1975;Numata et al, 1981;Howard-Lock et al, 1986). These results strongly suggested that the aldehydic functional …”

Section: After Incubation With [mentioning

confidence: 82%

Covalent Binding of Rofecoxib, but Not Other Cyclooxygenase-2 Inhibitors, to Allysine Aldehyde in Elastin of Human Aorta

Oitate¹,

Hirota²,

Murai³

et al. 2007

Drug Metab Dispos

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ABSTRACT:In rats, it has been reported that rofecoxib, a cyclooxygenase-2 (COX-2) inhibitor, reacts with the aldehyde group of allysine in elastin to give a condensation covalent adduct, thereby preventing the formation of cross-linkages in the elastin and causing degradation of the elastic fibers in aortas in vivo. Acid, organic solvent, and proteolytic enzyme treatments of human aortic homogenate after incubation with

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Hydralazine as an inhibitor of lysyl oxidase activity

Cited by 14 publications

References 10 publications

Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Comparing hydrazine-derived reactive groups as inhibitors of quinone-dependent amine oxidases

Covalent Binding of Rofecoxib, but Not Other Cyclooxygenase-2 Inhibitors, to Allysine Aldehyde in Elastin of Human Aorta

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