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

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638
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EFFECTS OF LUPUS-INDUCING DRUGS ON THE
B TO Z TRANSITION OF SYNTHETIC DNA
T. J. THOMAS and RONALD P. MESSNER
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-
~
_
_
From the Department of Medicine, Section of Rheumatology and Clinical Immunology, University of Minnesota School of
Medicine, Minneapolis.
Supported by NIH Training Grant no. AM-07437-03 and by
grants from the Minnesota Medical Foundation (CRF-70-85) and the
Minnesota Chapter of the Arthritis Foundation.
T. J . Thomas, PhD: Fellow; Ronald P. Messner, MD:
Professor and Director, Section of Rheumatology.
Address reprint requests to Ronald P. Messner, MD, Department of Medicine, Box 108, Mayo Building, University of
Minnesota, Minneapolis, MN 55455.
Submitted for publication July 31, 1985; accepted in revised
form November 4, 1985.
ArEhritis and Rheumatism, Vol. 29, No. 5 (May 1986)
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-ZDNA 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).
LU,PUS-INDUCING DRUGS AND B TO Z DNA TRANSITION
Prociainamide
Hydralazine
SH N H 2
I
1
L C H B )C
~-CHCOOH
D - Penicillamine
H2NC (= N H I N H O C H Z C H ~ C H
(NHZICO~H
lsoniazid
L - Canavanine
Figure 1. Chemical structures of the lupus-inducing drugs studied.
For Z-DNA to actually be formed by potentially
Z-DNA-forming sequences, certain environmental
conditions must be met. In in vitro studies using
synthietic polynucleotides, high concentrations of
NaCl or moderate concentrations of MgC12induce the
B to ;5 transition of poly(dG-dC) poly(dG-dC) and its
derivatives (10). Polyamines, which are ubiquitous in
all living cells, are also excellent B to Z transition
promloters at very low concentrations (18). These
compounds have charged amino groups (NH2+)which
react electrostatically with DNA phosphate and induce the transition. Because common SLE-inducing
drugs (19) also have charged amino groups (Figure l),
we undertook a study of the role of SLE-inducing
drugs in the B to Z transition of DNA.
639
(Milwaukee, WI). These polymers were dissolved in a buffer
containing 0.1M NaCI, 1 mM Na cacodylate, pH 7.4 (0.1M
NaCl buffer), and the solutions were dialyzed extensively
from the same buffer. A stock solution containing approximately 1 mg/ml of the polymer was stored at 4°C and diluted
from a buffer containing 1 mM NaCI, 1 mM Na cacodylate,
pH 7.4, for drug binding and B to Z transition studies.
Preparationof DNA-drug complexes. The stock DNA
solutions were diluted in 1 mM NaCI, 1 mM Na cacodylate,
0.3
pH 7.4, to approximately 10-15 pg/ml (absorbance
OD), and small volumes (5-25 pI) of a concentrated solution
of the drug in the same buffer were added to the DNA. The
solution was thoroughly mixed and kept overnight at 4°C to
complete the reaction.
Spectroscopic studies. Ultraviolet (UV) absorption
spectra of DNAs and the drugs were recorded on a Beckman
DU-8 spectrophotometer. Molar concentrations of the
DNAs were calculated from absorbance at 260 nm using
extinction coefficients (E) of 6,800 for calf thymus DNA and
8,400 for poly(dG-dC) . poly(dG-dC) and poly(dG-me’dC)
poly(dG-me’dC). Melting temperatures (Tm) were also
measured on a Beckman DU-8 spectrophotometer using the
Tm module by recording A2m versus temperature. The
midpoint of the transition region was taken as the Tm (20).
Circular dichroism (CD) spectra were recorded on a Jasco
5-41 spectropolarimeter using thermostated cells, with
poly(dG-me’dC) . poly(dG-me’dC) and calf thymus DNA at
concentrations of 4 x lO-’M and 6 x 10-5M, respectively.
The temperature variation during kinetic runs was *0.2”C.
2
MATERIALS AND METHODS
Drugs. Procainamide, N-acetyl procainamide, hydralazine, D-penicillamine, isoniazid, and L-canavanine
were purchased from Sigma (St. Louis, MO).
DNA. Calf thymus DNA was purchased from Sigma
and was dissolved in a buffer containing 0.15M NaCI, 1 mM
Na phosphate, pH 7.4 (0.15M NaCl buffer), at a concentration of approximately 1 mg/ml. After complete dissolution of
the DNA, the solution was extracted 3 times with phenol to
remove residual protein. The phenol-extracted DNA was
precipitated with absolute alcohol and then dissolved in
0.1.5M NaCl buffer. This DNA solution was then extensively
dialyzed from the same buffer. A stock solution containing
approximately 0.5 mglml of DNA was prepared and stored at
4°C. This solution was diluted in appropriate buffers for drug
binding studies.
Poly(dG-dC) . poly(dG-dC) and poly(dC-me’dC)
. poly(dG-me’dC) were purchased from P-L Biochemicals
225
250
275
300
325
W a v e i e n g t h . nm
Figure 2. Circular dichroism spectra of poly(dG-me5dC) . poly(dGme5dC)at 0.1M NaCl (right-handed [B] DNA) (solid line) and at 1M
NaCl (left-handed [Z] DNA) (broken line). Concentration of the
polymer was 4 x 10-5M.
THOMAS AND MESSNER
640
5
O-O-O-~
\lo--
e-e-•
0 c\I
0m
hi
a -5 w
Q
-10
1
I
I
I
225
250
275
I
300
Wavelength, nm
I
325
Figure 3. Circular dichroism spectra of calf thymus DNA at 0.IM
NaCI (solid line) and at 3M NaCl (broken line). DNA concentration
was 6 x 10-5M.
RESULTS
Since high concentrations of the drugs under
investigation absorb in the ultraviolet spectral region,
overlapping the UV and CD spectra of DNA, we
studied the effects of low concentrations of these drugs
on the salt-induced B to Z transition using CD spectroscopy. Poly(dG-meSdC) . poly(dG-meSdC)was used
in these studies because this polymer undergoes the B
t o Z transition at moderate NaCl concentrations (18).
Figure 2 shows the CD spectra of poly(dG-mesdC)
. poly(dG-meSdC) in the B and Z forms at 0.1M NaCl
and IM NaCI, respectively. The CD spectrum was
almost inverted when the salt concentration was increased from 0.1M to IM NaCI, characteristic of B to
Z transition (2 1). Under comparable conditions, calf
thymus DNA does not undergo any conformational
transition. However, at high NaCl concentrations
(3-5M), calf thymus DNA undergoes slight structural
I
I
perturbations within the right-handed family, the B to
C transition (22). This is shown by a reduction in the
CD spectral maximum at 280 nm (Figure 3).
The effects of chemical modification on the
polymer and of the addition of ligands on the saltinduced B to Z transition were studied by determining
the NaCl concentration required at the midpoint of the
transition, [NaCl],,dpolnt (18). As shown in Figure 4,
the concentration of NaCl required to induce the B to
Z transition was reduced in the presence of procainamide. In other words, procainamide facilitated the B
to Z transition of poly(dG-meSdC) . poly(dG-meSdC).
Similar effects occurred with hydralazine.
Findings on [NaCl],,dpolnt in the presence of
various drugs are presented in Table 1. N-acetyl
procainamide was used as a structurally related control for procainamide and was found to have no effect
on [NaCl]mldpolnt.
Similarly, the NaCl midpoint was not
altered with L-canavanine at a DNA phosphate:drug
Table 1. Effect of lupus-inducing drugs on the salt-induced B to
Z transition midpoint of poly(dG-me'dC) . poly(dG-me'dC)
Drug
DNA phosphate:
drug ratio
None
N-acetyl procainamide
Procainamide
H ydralazine
Isoniazid
D-penicillamine
20
20
20
20
20
"aCllm,dpomi
0.8
0.8
0.5
0.5
0.65
0.65
(M)
LUPUS-INDUCING DRUGS AND B TO Z DNA TRANSITION
641
r
+E
+2.5-
Time, man
0
(0
-
w-4
a &..z
.......... .......
C
0
a
-5
I
0
15
I
30
I
45
I
60
‘
75 /Y-
1
50
Time (minutes)
-10
I
1
1
I
I
225
250
275
300
325
3
W a v e l e n g t h , nm
Figure 5. Circular dichroism spectra of poly(dG-me5dC) . poly(dG
me5dC) at 1M NaCI, as a function of time.
ratio (P:D) of 20. We also found that the [NaCllml~polnt
of the unmethylated polymer, poly(dG-dC) * poly(dG
dC), could be reduced from 2.5M to 2.2M in the
presence of procainamide at a P:D of 20.
Since the change in [NaCll,,~po,nt might be
accompanied by changes in the rates of B to Z transition, we studied the time course of B to Z transition of
poly(dG-me’dC) . poly(dG-me5dC)in the presence and
abslence of lupus-inducing drugs at 1M NaCl. Figure 5
shows the CD spectra of poly(dG-me5dC) . poly(dG
me’dC) recorded at different times. The progression of
the negative band at 292 nm was used to evaluate the
kinetics of B to Z transition.
Figure 6 shows the kinetics of B to Z transition
of ]poly(dG-meSdC) poly(dG-me5dC) with different
concentrations of N-acetyl procainamide and procainamilde, and with the polymer without any drug. The
specific rate constants were calculated from the halftime (k = ln2/t4) and are plotted against the drug
concentration. The kinetic curve of poly(dG-meSdC)
poly(dG-me’dC) in the presence of N-acetyl procainamide could nearly be superimposed on that of the
polymer alone. However, increasing concentrations of
procainamide increased the rate of transition, up to a
concentration of 1 drug for 20 base pairs. Above this
drug concentration, the specific rate constant leveled
Figure 6. Kinetics of the B to Z transition of poly(dG-meSdC)
. poly(dG-me5dC) in the presence of procainamide and N-acetyl
procainamide at 1M NaCI. 0 = control, no drug; x = N-acetyl
procainamide, DNA phosphate:drug ratio (P:D) = 20; 0 =
procainamide, P:D = 80; A = procainamide, P:D = 40; A =
procainamide, P:D = 20; 0 = procainamide, PD = 15. Inset, specific
rate constant (k) plotted against procainamide ( 0 )and N-acetyl
procainamide ( X ) concentrations.
off. With N-acetyl procainamide, the specific rate
constant remained practically unchanged compared
with that of the polymer without any drug.
Table 2 presents the specific rate constants for
B to Z transition of poly(dG-meSdC) poly(dG-me5dC)
in the presence of all the drugs studied. Hydralazine
also caused an increase in the rate of B to Z transition
of poly(dG-me5dC) * poly(dG-me’dC). The other drugs
had only marginal effects.
We also studied the effect of procainamide and
hydralazine on the structural transitions of calf thymus
DNA. Since native DNAs do not undergo a global
right-handed to left-handed transition, we examined
the effect of these drugs on the double-stranded to
single-stranded transition, or the melting of calf thymus DNA. The melting points of DNA in the presence
of procainamide at 2 NaCl concentrations are presented in Table 3. Procainamide caused a reduction in
Tm at both ionic conditions. However, hydralazine did
not have any effect on the Tm of DNA.
We further observed that procainamide and
hydralazine induced the aggregation of calf thymus
DNA at high drug concentrations (about 1 drug per
base pair) by the appearance of a shoulder on the CD
spectra of calf thymus DNA at wavelengths above 300
nm. Since calf thymus DNA does not absorb at this
642
THOMAS AND MESSNER
Table 2. Effect of lupus-inducing drugs and L-canavanine on the
kinetics of B to Z transition of poly(dG-me5dC) . poly(dG-me5dC)
Drug and DNA
DhosDhate :drug ratio
Specific rate constant
x lo4. seconds-’
None
Procainamide
80
40
20
15
N-acetyl procainamide
80
40
20
H ydralazine
3.7
2
0.26*
-
4.1
7.2
7.2
7.7
3.9
4.2
3.8
no
4.4
5.0
5.0
40
20
Isoniazid
40
20
L-canavanine, 20
D-penicillamine, 20
3.9
4.1
3.9
4.1
* Control showed slight variation depending on the lot number of
poly(dG-me5dC) . poly(dG-me5dC),probably due to the polydispersity of the sample (LSD, n = 5). Variations in all other results were
within 25%.
wavelength, this shoulder formation has been attributed to the differential scattering of right or left circularly polarized light by DNA aggregates (23).
DISCUSSION
The results presented in this paper clearly show
that procainamide and hydralazine, 2 drugs associated
with the induction of SLE (19), facilitate the B to Z
transition of poly(dG-me’dC) . poly(dG-me’dC). Both
drugs reduce the concentration of NaCl required to
induce the transition and increase the rate of transition
at a given NaCl concentration. Isoniazid and D-
Table 3. Effect of procainamide on the melting temperature (Tm)
of calf thymus DNA
NaCl concentration
and DNA
phosphate:drug ratio
Tm (“C)*
0.075M
- (control)
40
0.15M
- (control)
40
* Values shown are mean 2
81
79
?
2
0.2
0.3
90 t 0.3
87 2 0.2
SD, n = 3.
penicillamine, 2 other drugs which are known to
induce SLE, affect the NaCl,i~p,,,t, but their effect on
the transition rate is less prominent. In contrast,
L-canavanine, which induces lupus in monkeys but
has not as yet been shown to do so in humans (24), has
no effect on the B to Z transition of poly(dG
me5dC) poly(dG-me’dC). The use of N-acetyl procainamide as a control for procainamide showed that
the acetylated compound does not have any effect on
the B to Z transition. This is important since acetyl
procainamide is not an SLE-inducing drug. Thus, the
effectiveness of these drugs in inducing the B to Z
transition appears to correlate with their SLE-inducing
efficacy.
Analysis of the possible mechanism responsible
for the drug-induced changes reveals a parallel between these results and those obtained with polyamines. It has recently been shown (25) that the acetyl
spermidines are much less effective in inducing the B
to Z transition of poly(dG-me5dC) * poly(dG-me’dC).
The charged amino group is thus a prerequisite for
inducing the B to Z transition. Our melting temperature studies showed that a reduction in Tm accompanied the procainamide-induced increase in the rate of
B to Z transition. This result is compatible with those
of recent studies in which a change in pH from 7.4 to
3.8 caused a reduction in the Tm of poly(dG-dC) .
poly(dG-dC) and a tenfold increase in the rate of B to
Z transition of this polymer (26). In the case of
hydralazine, covalent modification of the polymer may
play a role in facilitating the transition since
hydralazine is known to react with thymidine (27).
One central question emerges out of this study
and from recent reports on anti-Z-DNA antibodies in
SLE patient sera: What role does Z-DNA play in the
production of antinuclear antibodies in SLE patients?
It is known that SLE sera contain antibodies against a
host of nuclear components and that these antibodies
cross-react with a variety of proteins such as cardiolipin, cytoskeleton, and platelets (1-3). Native DNA is
a very weak antigen, and numerous attempts to raise
anti-native DNA antibodies with it, including immunization with poly(dG-dC) . poly(dG-dC) in the B
form, have failed (3). In contrast, altered forms of
DNA, such as UV-irradiated DNA and Z-DNA, are
effective antigens and readily elicit antibodies in experimental animals (8,28). Antibodies induced by altered DNA generally show specificity toward the
immunizing antigen (8,29,30), and thus have not provided a good model for the anti-native DNA autoantibodies present in SLE sera.
LUPUS-INDUCING DRUGS AND B TO Z DNA TRANSITION
Anti-Z-DNA antibodies also occur in SLE
(5,6). DNA from various sources, including SLE sera
(14), contains multiple copies of potentially Z-forming
sequences (12,13). In this context, it is interesting to
note that with negative supercoiling of plasmid DNA
con1aining inserts of Z-DNA-forming (dG-dC), (where
n 2 13), the B to Z transition readily occurs under
phy:jiologic ionic conditions (3 1,32).
Segments of Z-DNA also appear to exist in
native genomes such as the interband region of the
Drumphila polytene chromosome (9) and bacteriophage PM2 (33). It is further reported that DNA
isolarted from a few selected SLE patients contains a
higher percentage of G-C than that found in normal
controls (15,16). Thus, the induction of SLE in some
patients may involve the existence of an excess of
potentially Z-forming sequences in their DNA; this
would provide a prerequisite or permissive factor that
does not contribute to the disease process unless the
individual is exposed to conditions which will actually
induce the B to Z transition or which stabilize Z form
regions that occur spontaneously. These conditions
could arise endogenously from elevation of levels of
polyamines, as has been reported in SLE sera (34).
More pertinent to the results described in this paper,
they could also arise exogenously by administration of
SLE-inducing drugs or exposure to other chemicals
with these properties.
The conversion of B-DNA to Z-DNA even in a
segment of genomic DNA is accompanied by considerable structural variation. Z-DNA is more elongated
than B-DNA, with a rise per residue (phosphate to
phosphate distance) of 3.7A compared with 3.4A in the
B form (35,36). Similarly, Z-DNA is thinner, with a
diameter of 18A compared with 20A in B-DNA. ZDNA has also been shown to be less flexible than
B-DNA (37).
Since most of the eukaryotic DNA has been
packaged into chromatin, with histones as the major
stabilizing factor in the core particle, the formation of
a segment of Z-DNA in vivo implies that the core
histone octamer has to elongate to provide electrostatic and hydrophobic contact points to stabilize the
chromatin. Alternatively, it is possible that the 2-DNA
segment might dissociate from the core, thereby exposing both histones and DNA, since poly(dG-meSdC)
. poly(dG-meSdC) in the Z form fails t o form
nuclelosomes in reconstitution experiments under standard conditions (38). An explanation for the production of antihistone antibodies in drug-induced SLE
643
patients might thus lie in the altered conformationdpacking assembly of histones with drug-induced
Z-DNA segments, thereby making both DNA and
histones more immunogenic. In addition, the formation of a Z-form segment in native DNA generates a
junction between the B and Z forms. This junction has
been shown to exist in a partially single-stranded form
(39), and may provide a target for the production of
anti-ss DNA antibodies. Direct evidence for this and
for its applicability in at least certain cases of idiopathic and drug-induced lupus will require isolation
and sequencing of DNA from SLE patient sera, as well
as detailed studies on their conformational polymorphism and interactions with histones and other proteins.
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.
In summary, this study shows that procainamide and hydralazine cause considerable alterations
in the solution structure of poly(dG-meSdC) * poly(dG
mesdC) and in that of calf thymus DNA. With the
synthetic polymer, these drugs facilitate the B to Z
transition, whereas with calf thymus DNA, they affect
the melting transition and/or aggregation. These
changes might play a role in the production of antinuclear antibodies in patients with drug-induced SLE.
ACKNOWLEDGMWNTS
We wish to thank Dr. David Kiang, Section of
Medical Oncology, Department of Medicine, and Professor
Victor A. Bloomfield, Head, Department of Biochemistry,
University of Minnesota, for allowing us to use the Beckman
DU-8 spectrophotometers and Jasco J41 spectropolarimeter.
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THOMAS AND MESSNER
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