Dapsone-induced methemoglobinemia: a primer for clinicians.

OBJECTIVE: To present a comprehensive review of dapsone-induced methemoglobinemia and its management. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1966-March 2011), Cochrane Library, and EMBASE, using the terms dapsone and methemoglobinemia. STUDY SELECTION AND DATA EXTRACTION: All case reports, small case series, and randomized controlled trials published in English were evaluated. Because of the absence of comprehensive updates on this topic since 1996, publications between 1997 and March 2011 were included in this review. DATA SYNTHESIS: Between 1997 and March 2011, the majority of publications describing methemoglobinemia associated with dapsone use reported this adverse effect at therapeutic doses. Excluding overdose situations, 18 described symptomatic dapsone-associated methemoglobinemia and clinical presentation ranging from cyanosis to dyspnea. In almost all of the accounts, patients had a concurrent event such as anemia or pneumonia, suggesting an interplay between these comorbidities and the onset of symptomatic methemoglobinemia. Delayed hemolytic anemia was seen in patients with high methemoglobin levels at presentation. Management in most cases consisted of administration of methylene blue. Overall, most reports described a successful outcome, and no mortality resulted from methemoglobinemia associated with therapeutic use. CONCLUSIONS: Clinicians should recognize methemoglobinemia as an adverse effect associated with dapsone use and the potential factors that precipitate it. They should also know how to promptly and effectively manage this event.

T-cell receptor signaling is mediated by transient Lck activity, which is inhibited by inorganic mercury.

Genetically susceptible rodents exposed to low nontoxic levels of inorganic mercury (Hg(2+)) develop idiosyncratic autoimmune disease associated with defective T-cell function. However, the molecular mechanisms underlying this phenomenon remain mostly unexplained. Brief exposure of T cells to micromolar concentrations of Hg(2+) leads to physiologically relevant nontoxic cellular mercury burdens, and as we have previously reported, attenuates T-cell receptor (TCR) signal strength by approximately 50%. We have found this to be the result of an inadequate activation of the tyrosine kinase ZAP-70, which is hypophosphorylated following TCR stimulation in Hg(2+) burdened cells when compared to untreated controls. In T cells, ZAP-70 phosphorylation is dependent on lymphocyte-specific protein tyrosine kinase (Lck) activity, which in turn is either positively or negatively regulated by the phosphorylation of specific Lck tyrosine residues. In particular, the general belief is that Lck is negatively regulated by phosphorylation of tyrosine 192 (Y192). We now demonstrate by Western blotting that, in Jurkat T cells, TCR signal transduction (and ZAP-70 phosphorylation) was positively associated with a rapid transient phosphorylation of Y192, which was inhibited in cells that were briefly (5 min) exposed to 5 microM Hg(2+). Thus, Hg(2+) inhibits a critical activating role played by Lck Y192 during the most proximal events of the TCR-induced cell signaling.

Inorganic mercury inhibits the activation of LAT in T-cell receptor-mediated signal transduction.

Little is known as to the molecular mechanisms involved with mercury intoxication at very low levels. Although the mechanism is not known, animal studies have nevertheless shown that low levels of mercury may target the immune system. Inorganic mercury (Hg2+) at very low (but non-toxic) levels can disrupt immune system homeostasis, in that genetically susceptible rodents develop idiosyncratic autoimmune disease, which is associated with defective T-cell function. T lymphocyte function is intimately coupled to the T-cell receptor. We have previously reported that on a molecular level, low concentrations of Hg2+ disrupt signaling from the T-cell receptor by interfering with activation of Ras and ERK MAP kinase. In this report we expand upon those results by showing that in T lymphocytes exposed to low concentration of Hg2+, Ras fails to become properly activated because upstream of Ras in the T cell signal transduction pathway, the important scaffolding element Linker for Activation of T Cells (LAT) fails to become properly phosphorylated. Hypo-phosphorylation of LAT occurs, because upstream of LAT, the LAT reactive tyrosine kinase ZAP-70 is also not properly activated in Hg2+ treated cells.

Inorganic mercury dissociates preassembled Fas/CD95 receptor oligomers in T lymphocytes.

Genetically susceptible rodents exposed to low burdens of inorganic mercury (Hg2+) develop autoimmune disease. Previous studies have shown that low, noncytotoxic levels of Hg2+ inhibit Fas-mediated apoptosis in T cells. These results suggest that inhibition of the Fas death receptor pathway potentially contributes to autoimmune disease after Hg2+ exposure, as a consequence of disruption of peripheral tolerance. The formation of active death inducing signaling complexes (DISC) following CD95/Fas receptor oligomerization is a primary step in the Fas-mediated apoptotic pathway. Other recent studies have shown that Hg2+ at concentrations that inhibit apoptosis also inhibit formation of active DISC, suggesting that inhibition of DISC is the mechanism responsible for Hg2+-mediated inhibition of apotosis. Preassociated Fas receptors have been implicated as key elements necessary for the production of functional DISC. We present evidence in this study showing that low and nontoxic concentrations of Hg2+ induce the dissociation of preassembled Fas receptor complexes in Jurkat T cells. Thus, this Hg2+-induced event should subsequently decrease the amount of preassembled Fas available for DISC formation, potentially resulting in the attenuation of Fas-mediated apoptosis in T lymphocytes.