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Drug acetylation phenotype unrelated to development of spontaneous systemic lupus erythematosus.

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777
DRUG ACETYLATION PHENOTYPE
UNRELATED TO DEVELOPMENT OF
SPONTANEOUS SYSTEMIC LUPUS ERYTHEMATOSUS
RICHARD J. MORRIS, CURT R. FREED, and PETER F. KOHLER
To ascertain if a genetically determined slow
drug acetylation rate is correlated with the development
of spontaneous systemic lupus erythematosus (SLE), as
it is in drug-induced SLE, acetylation phenotypes of 27
patients with spontaneous SLE were determined after
administration of dapsone. Thirty-three percent were
slow acetylators, 63%were rapid acetylators, and one
was indeterminate, a distribution not signi6cantly different from that expected in control subjects. Among 4
pairs of firstdegree relatives, all of whom had spontaneous SLE, 7 of the 8 individuals were rapid acetylators.
We conclude that people who are slow acetylators are
at no greater risk for developing spontaneous SLE than
are rapid acetylators and that the slow acetylation
phenotype is not correlated with familial SLE.
The clinical features of systemic lupus erythematosus (SLE) appear without apparent etiology in patients with “spontaneous” S L E these same features also
occur in some patients exposed to drugs, especially
hydralazine, procainamide, and isoniazid (1,2). DifferFrom the Divisions of Clinical Immunology and Clinical
Pharmacology, The University of Colorado Medical Center, Denver,
Colorado 80262.
Publication number 3 of the Lupus Study Group at The University of Colorado Medical Center.
Supported by a General Clinical Research Center Program
Grant (#RR51), a training grant’(A107166), and donations from the
Colorado Lupus Foundation.
Richard J. Moms, MD, Curt R. Freed, MD: recipient of a
Faculty Development Award from the Pharmaceutical Manufacturer’s Foundation (CRF); Peter F. Kohler, MD.
Address reprint requests to Dr. P. F. Kohler, MD, Division
of Clinical Immunology, Box B- 164, University of Colorado Medical
Center, 4200 East Ninth Avenue, Denver, Colorado 80262.
Submitted for publication November 29, 1978; accepted in
revised form February 1, 1979.
Arthritis and Rheumatism, Vol. 22, No. 7 (July 1979)
ences in the clinical findings include less severe central
nervous system dysfunction and renal disease in druginduced SLE (3). Laboratory evaluation shows antibodies to acidic nuclear proteins in spontaneous SLE,
whereas antibodies to nuclear histones are predominant
in the drug-induced form (4).
Each of the drugs which cause a lupus-like disorder is metabolized by hepatic N-acetyl transferase.
The activity of this enzyme is genetically determined by
two autosomal alleles, and individuals can be phenotypically characterized as “slow” or “rapid” acetylators
by measurement of drug acetylation rates. Population
and family studies are consistent with the theory that
the allele for slow acetylation is recessive and the one
for rapid acetylation is dominant (5). The allele frequencies can be derived from the observed Occurrence
of slow acetylators (homozygous recessive) in a given
study population. In North American blacks and
whites, the frequency of the slow allele is 0.72 and the
rapid is 0.28. Given these frequencies, a simple Mendelian inheritance pattern results in the observed incidence of 52% slow acetylators in this population.
Recent studies indicate that drug-induced SLE
occurs with a higher incidence and after less drug exposure in slow acetylators than in rapid acetylators
(2,6). Investigatorsbelieve that the greater persistence in
the body of procainamide is responsible for inducing
lupus in some people. Although spontaneous SLE has
features distinct from drug-induced SLE, four reports
(7- 10) have been published suggesting that spontaneous
SLE patients are also predominantly slow acetylators of
drugs (68-100370). However, Vasant et a1 (11) have recently published a dissenting opinion: of their 18 patients, 9 were fast acetylators, 8 were slow, and l was in-
MORRIS ET AL
778
2.5
1J
2.0
0.5
4
RESULTS
0
0
0
7 rapid acetylotion
The monoacetyl dapsone to dapsone ratios of the
27 patients are presented in Figure 1. Nine patients
(33%) were slow acetylators, 17 (63%) were rapid acetylators, and 1 was indeterminate. Chi-square analysis
shows that this distribution is not significantly different
(P = 0.12) from the expected 52% slow acetylators reported in studies on North American and European
subjects (5,12). The proportion of rapid acetylator
phenotype in the different racial groups was black 2/4
(50%), Mexican-American 7/8 (88%), and white 8/14
(57%). One white patient’s phenotype was indeterminant (MAD/DDS = 0.34, Figure 1).
Among our SLE patients were 4 pairs of first-degree relatives: 3 sibling pairs, and a mother and son.
Their acetylator phenotypes are presented in Table 1.
Of the sibling pairs, 2 were concordant for rapid acetylation, and one was discordant (one rapid and one slow).
The mother and son were both rapid acetylators.
Figure 1. Ratio of rnonoacetyl dapsone (MAD) to dapsone (DDS) in
27 patients with SLE.
determinate. This distribution is essentially the same as
expected in non-SLE controls (12). Thus, there is some
controversy over the relevance of acetylator status to the
development of SLE.
To help resolve this issue, we have studied the
acetylation rate of dapsone in 27 patients with spontaneous SLE, including 4 pairs of first degree relatives.
PATIENTS AND METHODS
Twenty-seven patients with definite systemic lupus
erythematosus were studied in the Clinical Research Center at
the University of Colorado Medical Center. Criteria for diagnosis of SLE were those of the American Rheumatism Association (13) and the presence of antinuclear antibodies, anti-native-DNA antibodies, and low serum complement. There were
21 females and 6 males whose ages ranged from 12 to 56
years. Four patients were black, 8 were Mexican-American,
and 15 were white. One patient was receiving phenytoin, but
this drug had been started after the onset of her disease. All
patients were clinically stable when studied.
Acetylator phenotype was determined by the high
performance liquid chromatography method of Carr et a1 (14)
which measures the ratio of monoacetyl dapsone (MAD) to
dapsone (DDS) in the serum of patients 3 hours after ingestion of 100 mg of dapsone. This procedure has been validated
on 24 healthy white volunteers, as previously reported (14). A
ratio of greater than 0.35 was used to indicate rapid acetylation; less than 0.30 was determined slow acetylation; and between 0.30-0.35 was considered indeterminate (6,15). All
probabilities were computed by the chi-square method with
the Yates correction (16).
DISCUSSION
People who are phenotypically slow acetylators
are at greater risk than rapid acetylators for developing
a drug-induced lupus syndrome (2,6). This observation
has given rise to the theory that spontaneous SLE may
also be more common in slow acetylators, possibly as a
consequence of exposure to as yet undetermined environmental toxins that persist due to slow acetylation.
Four studies (7-10) have purported to show a preponderance of slow acetylators in spontaneous SLE patients. Fishbein and Alarcon-Segovia (7) studied isoniazid acetylation in 25 SLE patients and 153 tuberculous
controls. They found 18 of the SLE patients (72%) and
51% of the controls to be slow acetylators. The other 7
SLE patients were “intermediate,” suggesting a triTable 1. Acelylator phenotype of first-degree relatives
Patient
Phenotype
Siblings
JR
NC
slow
rapid
HL
AL
rapid
rapid
LN
CM
rapid
rapid
Mother/son
TG
RG
rapid
rapid
ACETYLATION PHENOTYPE AND SLE
779
modal distribution for isoniazid acetylation (17). Foad
et a1 (8) used sulfamethazine acetylation in 25 SLE patients and found 17 slow acetylators (68%), but this incidence was not significantly different from the expected
52% (P = 0.16). In a study from Finland, Johansson et
a1 (9) studied 42 patients by using sulfamethazine, and
they found 29 (69%) slow acetylators. However, these
investigators did not describe their patient population;
in particular, they did not state whether they all developed SLE spontaneously or whether there were any
family clusters included. Since they did not report the
acetylator phenotype distribution on non-SLE controls
in Finland, and since there are known differences
among ethnic and national populations (12), meaningful comparison between their data and ours is not possible. Reidenberg and Martin (10) reported dapsone
acetylation rates of 14 SLE patients. Ten were definitely
slow (MAD/DDS < 0.30). They called 2 patients “indeterminate” who had ratios of 0.37 and 0.43, despite a
previous publication of theirs (15 ) in which those over
0.35 were classified as rapid acetylators. Applying the
0.35 cutoff to their patients leads to the conclusion that
4 of their 14 patients were rapid acetylators, which is
not significantly different from the expected (P= 0.18).
If the two are called indeterminate and excluded from
the calculations, then the results achieve statistical significance.
In our study of 27 patients, the majority (63%)
were rapid acetylators. This distribution was not significantly different from the expected 52% slow acetylators
(P = 0.12) and agrees with the findings of Vasant et a1
(1 1).
Other than the above comments, it is d a c u l t to
reconcile our results with those reports that indicate
slow acetylator predominance in spontaneous SLE. Our
choice of dapsone as a drug to be acetylated differs from
some of the earlier studies which used isoniazid (7) or
sulfamethazine (8,9). Reidenberg and Martin (10) and
Vasant et a1 (1 1) used dapsone. Gelber et a1 (18) have
shown that the acetylation characteristics of all three
drugs are similar, and they and others (12) have proved
that the acetylator phenotype of an individual does not
vary with time. In addition, it has been shown (18) that
the plasma ratio of MAD:DDS is virtually identical at
4, 6, and 8 hours. Therefore, it is unlikely that the
choice of drug or temporal variations account for the divergent results in the several studies.
As mentioned, our 27 patients included 4 related
pairs with SLE. Seven of these 8 individuals were rapid
acetylators, It is probable that SLE occurring in family
clusters has a more significant genetic basis than SLE
arising apparently at random in unrelated individuals.
If only the 19 unrelated patients in our study are considered, there were 10 rapid, 8 slow, and 1 indeterminate
acetylators, essentially what would be expected from the
phenotype distribution of the general population.
These data and a critical review of the previously
published reports indicate to us that people who are
slow drug acetylators are at no greater risk for developing spontaneous SLE than are rapid acetylators.
REFERENCES
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Semin Hematol 10345, 1973
2. Perry HM Jr, Tan EM, Carmody S, et al: Relationship of
acetyl transferase activity to antinuclear antibodies and
toxic symptoms in hypertensive patients treated with
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3. Lee SL, Chase PH: Drug-induced systemic lupus erythematosus: a critical review. Semin Arthritis Rheum
5233, 1975
4. Fritzler MJ, Tan EM: Antibodies to histones in drug-induced and idiopathic lupus erythematosus. J Clin Invest,
in press
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of isoniazid metabolism in man. Br Med J 2:485491,
1960
6. Woosley RL, Drayer DE, Reidenberg MM, et al: Effect of
acetylator phenotype on the rate at which procainamide
induces antinuclear antibodies and the lupus syndrome.
N Engl J Med 298:1157,1978
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erythematosus (abstract). Arthritis Rheum 19:796, 1976
8. Foad B, Litwin A, Zimmer H, et al: Acetylator phenotype
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1977
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Clin Res 8: 126, 1976
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patients with systemic lupus erythematosus. Drug Metab
Dispos 2:7 1, 1974
11. Vasant J, Woosley RL, John JT, et a 1 Normal distribution of acetylation phenotypes in systemic lupus erythematosus. Arthritis Rheum 21:192, 1978
12. Kalow W Pharmacogenetics: Heredity and the Response
to Drugs. Philadelphia, Saunders, 1962, pp 95-100
13. Cohen AS, Reynolds WE, Franklin EC, et al: Preliminary
780
criteria for classificationof systemic lupus erythematosus.
Bull Rheum Dis 21:643, 1971
14. Cam K, Oates JA, Nies AS, et a1 Simultaneous analysis
of dapsone and monacetyl dapsone employing hgh performance liquid chromatography: a rapid method for determination of acetylator phenotype. Br J Clin Pharm
6421427, 1978
15. Reidenberg MM, Drayer DE, DeMarco AL, et a1 Hy-
MORRIS ET AL
dralazine elimination in man. Clin Pharmacol Ther
14:97&977, 1973
16. Snedecor GW: Statistical Methods. Fifth edition. Ames,
Iowa, Iowa State University Press, 1956
17. Fishbein E, Alarc6n-Segovia D: Personal communication
18. Gelber R, Peters JH, Gordon GR, et al:The polymorphic
acetylation of dapsone in man. Clin Pharmacol Ther
12~225-238,1971
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development, lupus, unrelated, acetylation, drug, spontaneous, phenotypic, systemic, erythematosus
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