The interaction of lupus-inducing drugs with deoxyribonucleic acid

Eldredge, Noreen T.; Robertson, W. W.; Miller, John J.

doi:10.1016/0090-1229(74)90014-2

Cited by 43 publications

(7 citation statements)

References 12 publications

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“…The aggregation effect of procainamide and hydralazine, demonstrated in this study by the CD spectral changes at wavelengths above 300 nm and previously reported by Eldredge et al (40), might also contribute to the production of antibodies. If the serum level of circulating DNAs is very low, as has been shown in recent studies (41), it is quite possible that concentrations of procainamide or hydralazine in the sera reach the order of 1 drug molecule per base pair, similar to the drug:DNA ratio at which aggregation was observed in our study.…”

Section: Discussionsupporting

confidence: 86%

Effects of lupus‐inducing drugs on the B to Z transition of synthetic DNA

Thomas

Messner

1986

Arthritis & Rheumatism

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Five drugs associated with systemic lupus erythematosus were studied for their effect on the salt-induced right-handed (B) to left-handed (Z) transition of poly (dG-me5dC) . poly(dG-me5dC). Using circular dichroism spectroscopy, procainamide and hydralazine were found to reduce the midpoint of B to Z transition from 0.8M NaCl to 0.5M NaCl and to increase the rate of this transition at 1M NaCI. Isoniazid and D-penicillamine had less effect on the midpoint of transition and practically no effect on the kinetics. N-acetyl procainamide (a structurally related control for procainamide) and L-canavanine had no effect. Procainamide caused slight reduction in the helix-coil transition (melting) temperature of calf thymus DNA. At a concentration of 1 : 1 (DNA phosphate : drug ratio), procainamide and hydralazine also caused the aggregation of calf thymus DNA. Since altered DNA conformations, such as Z-DNA, are more immunogenic, these results suggest that the induction or stabilization of Z-DNA by these drugs might be important in the pathogenesis of at least some cases of systemic lupus erythematosus.The presence of a variety of antibodies showing differing degrees of specificity to nuclear components-DNA, RNA, histones-is the hallmark of idio- pathic and drug-induced systemic lupus erythematosus (SLE) ( 1 4 ) . In addition to antibodies against right-handed (B) DNA and single-stranded (ss) DNA, recent reports indicate the presence of antibodies to left-handed (Z) DNA in SLE patient sera (5,6). Antibodies raised from the autoimmune MRL/lpr-lpr mouse strain also show specificity for different forms of Z-DNA (7). Z-DNA is an effective antigen, as demonstrated by Lafer et a1 (8), who produced anti-Z-DNA antibodies by exogenous administration of brominated poly(dG-dC) . poly(dG-dC) in mice and rabbits. Using these antibodies, the presence of segments of Z-DNA has been revealed in some native genomes, such a s the interband region of the Drosophila polytene chromosome (9).The DNA sequences which are capable of converting to the Z form in the presence of salts, alcohols, and polyamines are mainly constituted of alternating purine-pyrimidines: specifically, dG-dC and its derivatives (10). However, DNA sequences consisting of (dT-dG), . (dC-dA), also undergo the right-handed to left-handed transition upon covalent modification with drugs such as acetylaminofluorene (1 1). These potential Z-DNA-forming sequences are widely dispersed in the human genome (12) and other native DNAs (13). Van Helden (14) recently reported that DNA fragments isolated from the serum of an SLE patient were rich in these potentially Z-DNA-forming regions. Similarly , Sano and Morimoto (1 5,16) reported that DNA fragments isolated from DNA-anti-DNA immune complexes contained a higher percentage of guaninecytosine (G-C) sequences compared with the average percentage of such sequences in total human DNA (5040% versus 38%). In addition, SLE sera show a high binding affinity for DNA fragments containing elevated G-C content or Z-form conformation (17).

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Section: Discussionsupporting

confidence: 86%

Effects of lupus‐inducing drugs on the B to Z transition of synthetic DNA

Thomas

Messner

1986

Arthritis & Rheumatism

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“…Individuals that develop this reaction have antinuclear antibodies as well as antibodies to DNA and nucleoproteins (6)(7)(8)(9)(10)(11)(12)(13). In vitro studies have also demonstrated interaction of systemic lupus erythematosus-inducing drugs with DNA (11,14,15).In the metabolism ofxenobiotics, N-acetylation is a step that can be followed by reactions such as N-hydroxylation and esterification, resulting in the generation of reactive metabolites that undergo covalent binding with cellular macromolecules, including DNA (16,17). Chemicals that can be acetylated and that also form covalent adducts with DNA include procainamide (18,19), isoniazid (20), and hydralazine (15), as well as the aromatic amine carcinogens, benzidine (21, 22), 2-aminofluorene, and 4-aminobiphenyl (23).…”

mentioning

confidence: 99%

Relationship between the genetically determined acetylator phenotype and DNA damage induced by hydralazine and 2-aminofluorene in cultured rabbit hepatocytes.

McQueen

Maslansky

Glowinski

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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The relationship between acetylation rates of rabbit hepatocytes and their susceptibility to genotoxicity by DNAdamaging chemicals that undergo N-acetylation was studied in primary cultures of hepatocytes from New Zealand White rabbits that have a genetically determined difference in acetylation rates. Hepatocytes from rapid and slow acetylator rabbits maintained in culture the difference in acetylation rates that existed in viva DNA repair, an index of DNA damage, was produced by hydralazine in hepatocytes from slow acetylator rabbits but not in those from rapid acetylators. In contrast to these results, hepatocytes from rapid acetylators were more sensitive than those from slow acetylators to toxicity from the carcinogen 2-aminofluorene and displayed greater amounts of DNA repair. The amount of DNA repair measured with either chemical was dose dependent. These phenotype-dependent differences in the genotoxicity of two DNAdamaging chemicals provide evidence for the role of the acetylation polymorphism as a factor in determining susceptibility to toxicity, and perhaps carcinogenicity, of these chemicals. N-Acetylation rates of xenobiotics are under polymorphic genetic control in both humans and rabbits, resulting in individuals being either rapid or slow acetylators (1-5). This trait has been linked to toxicity and damage to DNA by chemicals of the aromatic amine or hydrazine type (6). For example, slow acetylator individuals are more likely than rapid acetylators to develop drug-related systemic lupus erythematosus (6-8). Individuals that develop this reaction have antinuclear antibodies as well as antibodies to DNA and nucleoproteins (6)(7)(8)(9)(10)(11)(12)(13). In vitro studies have also demonstrated interaction of systemic lupus erythematosus-inducing drugs with DNA (11,14,15).In the metabolism ofxenobiotics, N-acetylation is a step that can be followed by reactions such as N-hydroxylation and esterification, resulting in the generation of reactive metabolites that undergo covalent binding with cellular macromolecules, including DNA (16,17). Chemicals that can be acetylated and that also form covalent adducts with DNA include procainamide (18,19), isoniazid (20), and hydralazine (15), as well as the aromatic amine carcinogens, benzidine (21, 22), 2-aminofluorene, and 4-aminobiphenyl (23). Adduct formation by chemicals can be mediated by the enzymatic removal of the N-acetyl moiety (24,25), and evidence in the rabbit suggests that this reaction and the initial acetylation step are properties of the same enzyme (26).Because a difference in the acetylation rate can alter the proportion ofspecific metabolites that are formed (27), it is possible that genotoxicity-i. e., damage to DNA (28)-by substrates of N-acetyltransferase could be affected by the amount of acetylation. In order to investigate this possibility, we developed a model system that permitted measurement of both N-acetyltransferase activity and DNA damage in the same cells, using hepatocytes, which represent a major tissue of acetylation (...

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“…Evidence for an interaction of Hy and Pr with DNA (Eldredge et al, 1974) or histone-DNA complexes (Tan, 1968) has been obtained in vitro. Other studies (Kirtland et al, 1980) have demonstrated an inhibitory effect of drugs on the function of suppressor T lymphocytes.…”

Section: Methods and Resultsmentioning

confidence: 95%

Nephrotoxic Mechanisms of Drugs and Environmental Toxins

Porter¹

1982

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The interaction of lupus-inducing drugs with deoxyribonucleic acid

Cited by 43 publications

References 12 publications

Effects of lupus‐inducing drugs on the B to Z transition of synthetic DNA

Effects of lupus‐inducing drugs on the B to Z transition of synthetic DNA

Relationship between the genetically determined acetylator phenotype and DNA damage induced by hydralazine and 2-aminofluorene in cultured rabbit hepatocytes.

Nephrotoxic Mechanisms of Drugs and Environmental Toxins

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