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Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus.

ABSTRACT: Accumulating evidence indicates that epigenetic alterations contribute to exacerbated activation or deregulation of the mechanisms that maintain tolerance to self-antigens in patients with lupus, a systemic autoimmune disease that can be triggered by medications taken to treat a variety of conditions. Here, we tested the effect of hydralazine, an antihypertensive drug that triggers lupus, on receptor editing, a chief mechanism of B lymphocyte tolerance to self-antigens. Using mice expressing transgenic human Igs, we found that hydralazine impairs up-regulation of RAG-2 gene expression and reduces secondary Ig gene rearrangements. Receptor editing was also partially abolished in a dose-dependent manner by a specific inhibitor of MEK1/2. Adoptive transfer of bone marrow B cells pretreated with hydralazine or with a MEK inhibitor to naïve syngeneic mice resulted in autoantibody production. We conclude that, by disrupting receptor editing, hydralazine subverts B lymphocyte tolerance to self and contributes to generation of pathogenic autoreactivity. We also postulate that inhibition of the Erk signaling pathway contributes to the pathogenesis of hydralazine-induced lupus and idiopathic human lupus.

SUBMITTER: Mazari L

PROVIDER: S-EPMC1851062 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus.

Mazari Lynda L Ouarzane Meryem M Zouali Moncef M

Proceedings of the National Academy of Sciences of the United States of America 20070402 15

Accumulating evidence indicates that epigenetic alterations contribute to exacerbated activation or deregulation of the mechanisms that maintain tolerance to self-antigens in patients with lupus, a systemic autoimmune disease that can be triggered by medications taken to treat a variety of conditions. Here, we tested the effect of hydralazine, an antihypertensive drug that triggers lupus, on receptor editing, a chief mechanism of B lymphocyte tolerance to self-antigens. Using mice expressing tra ...[more]

PMID: 17404230

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Project description:BackgroundDespite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity.SummaryThere is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.

Dataset Information

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus.

Publications

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus.

Similar Datasets

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