Homozygous gene deletions of the glutathione S-transferases M1, and T1 areassociated with thimerosal sensitization

Objective: Thimerosal is an important preservative in vaccines and ophthalm ologic preparations. The substance is known to be a type IV sensitizing age nt. High sensitization rates were observed in contact-allergic patients and in health care workers who had been exposed to thimerosal-preserved vaccin es. There is evidence for the involvement of the glutathione system in the metabolism of thimerosal or its decomposition products (organomercury alkyl compounds). Thus detoxification by polymorphically expressed glutathione S -transferases such as GSTT1 and GSTM1 might have a protective effect agains t sensitization by these substances. Methods: To address this question, a c ase control study was conducted, including 91 Central European individuals with a positive patch-test reaction to thimerosal. This population was comp ared with 169 healthy controls and additionally with 114 individuals affect ed by an allergy against para-substituted aryl compounds. The latter popula tion was included in order to test whether possible associations were due t o substance-specific effects, or were a general feature connected with type IV immunological diseases. Homozygous deletions of GSTT1 and GSTM1 were de termined by polymerase chain reaction. Results: Glutathione S-transferase M 1 deficiency was significantly more frequent among patients sensitized to t himerosal (65.9%, P = 0.013) compared with the healthy control group (49.1% ) and the "para-compound" group (48%, P = 0.034). Glutathione S-transferase T1 deficiency in the thimerosal/mercury group (19.8%) was barely elevated versus healthy controls (16.0%) and the "para-compound" group (14.0%). The combined deletion (GSTT1-/GSTM1-) was markedly more frequent among thimeros al-sensitized patients than in healthy controls (17.6% vs. 6.5%, P = 0.0093 ) and in the "para-compound" group (17.6% vs. 6.1%; P = 0.014), revealing a synergistic effect of these enzyme deficiencies (healthy controls vs. thim erosal GSTM1 negative individuals, OR = 2.0 [CI = 1.2-3.4], GSTT1-, OR = 1. 2 [CI = 0.70-2.1], GSTM1/T1-, OR = 3.1 [CI = 1.4-6.5]). Conclusions: Since the glutathione-dependent system was repeatedly shown to be involved in the metabolism of thimerosal decomposition products, the observed association may be of functional relevance.