Hydralazine induces Z-DNA conformation in a polynucleotide and elicits anti(Z-DNA) antibodies in treated patients

Thomas, Thresia; Seibold, James R.; Adams, Louis E.; Hess, Evelyn V.

doi:10.1042/bj2940419

Cited by 22 publications

(10 citation statements)

References 49 publications

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“…Sequence and conformational specificity has been observed in these interactions. Our results have specifically revealed that hydralazine binds with high affinity to DNA sequences capable of assuming the Z-DNA conformation [5]. Potential Z-DNA-forming alternating purine-pyrimidine sequences are widely dispersed in native DNAs and their frequency of occurrence is far higher in DNA isolated from the serum of lupus patients compared with normal controls [10,11].…”

Section: Introductionmentioning

confidence: 89%

“…This adverse effect has reduced its usage as an antihypertensive drug, at least with larger doses. Among the anti-nuclear antibodies elicited by hydralazine, anti-histone antibodies are the most prominent; however, antibodies reacting with single-stranded and Z-DNA are also found in the serum of patients taking this drug [4][5][6]. The origin of these antibodies in the serum of drug-treated patients is not known at present.…”

Section: Introductionmentioning

confidence: 98%

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Triplex-DNA stabilization by hydralazine and the presence of anti-(triplex DNA) antibodies in patients treated with hydralazine

Thomas¹,

Seibold²,

Adams

et al. 1995

Biochemical Journal

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Hydralazine is an antihypertensive drug that elicits andti-nuclear antibodies in patients as an adverse effect. We investigated the ability of hydralazine to promote/stabilize the triplex DNA form of poly(dA).2poly(dT). Under conditions of low ionic strength, the polynucleotide melted as a double helix with a melting temperature (Tm) of 55.3 degrees C. Hydralazine destabilized this duplex form by reducing its Tm to 52.5 degrees C. Spermidine (2.5 microM), a natural polyamine, provoked the triplex form of poly(dA)-.2poly(dT) with two melting transitions, Tm1 of 42.8 degrees C corresponding to triplex-->duplex+single-stranded DNA and Tm2 of 65.4 degrees C, corresponding to duplex melting. Triplex DNA thus formed in the presence of spermidine was further stabilized by hydralazine (250 microM) with a Tm1 of 53.6 degrees C. A similar stabilization effect of hydralazine was found on triplex DNA formed in the presence of 5 mM Mg2+. CD spectra revealed conformational perturbations of DNA in the presence of spermidine and hydralazine. These results support the hypothesis that hydralazine is capable of stabilizing unusual forms of DNA. In contrast with the weak immunogenicity of DNA in its right-handed B-DNA conformation, these unusual forms are immunogenic and have the potential to elicit anti-DNA antibodies. To test this possibility, we analysed sera from a panel of 25 hydralazine-treated patients for anti-(triplex DNA) antibodies using an ELISA. Our results showed that 72% of sera from hydralazine-treated patients contained antibodies reacting toward the triplex DNA. In contrast, there was no significant binding of normal human sera to triplex DNA. Taken together our data indicate that hydralazine and related drugs might exert their action by interacting with DNA and stabilizing higher-order structures such as the triplex DNA.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 98%

Triplex-DNA stabilization by hydralazine and the presence of anti-(triplex DNA) antibodies in patients treated with hydralazine

Thomas¹,

Seibold²,

Adams

et al. 1995

Biochemical Journal

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“…Polyamines are increased in the sera of children with SLE [63]. Hydralazine induced lupus also stabilizes Z-DNA indicating that its inhibition of the ERK pathway plays a role in Z-DNA stabilization or it affects polyamine synthesis [64]. …”

Section: Dna Modificationsmentioning

confidence: 99%

Metabolic control of the epigenome in systemic Lupus erythematosus

Oaks

Perl

2013

Autoimmunity

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Epigenetic mechanisms are proposed to underlie aberrant gene expression in systemic lupus erythematosus (SLE) that results in dysregulation of the immune system and loss of tolerance. Modifications of DNA and histones require substrates derived from diet and intermediary metabolism. DNA and histone methyltransferases depend on S-adenosylmethionine (SAM) as a methyl donor. SAM is generated from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase (MAT), a redox-sensitive enzyme in the SAM cycle. The availability of B vitamins and methionine regulate SAM generation. The DNA of SLE patients is hypomethylated, indicating dysfunction in the SAM cycle and methyltransferase activity. Acetyl-CoA, which is necessary for histone acetylation, is generated from citrate produced in mitochondria. Mitochondria are also responsible for de novo synthesis of flavin adenine dinucleotide (FAD) for histone demethylation. Mitochondrial oxidative phosphorylation is the dominant source of ATP. The depletion of ATP in lupus T cells may affect MAT activity as well as adenosine monophosphate (AMP) activated protein kinase (AMPK), which phosphorylates histones and inhibits mechanistic target of rapamycin (mTOR). In turn, mTOR can modify epigenetic pathways including methylation, demethylation, and histone phosphorylation and mediates enhanced T-cell activation in SLE. Beyond their role in metabolism, mitochondria are the main source of reactive oxygen intermediates (ROI), which activate mTOR and regulate the activity of histone and DNA modifying enzymes. In this review we will focus on the sources of metabolites required for epigenetic regulation and how the flux of the underlying metabolic pathways affects gene expression.

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“…Another characteristic of the DNA in SLE patients' sera is that it can potentially form Z-DNA [83]. Hydralazing demethylating agents are able to induce Z-DNA conformation in vitro and elicit anti-Z-DNA Ab production in treated patients [84]. Polyamines (spermidine and spermine) that can bind to and stabilize Z-DNA structure and interfere with the DNA methylation process are also increased in SLE [85].…”

Section: Epigenetic Modifications and Autoantibodiesmentioning

confidence: 99%