Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization.
OBJECTIVE
Thimerosal is an important preservative in vaccines and ophthalmologic preparations. The substance is known to be a type IV sensitizing agent. High sensitization rates were observed in contact-allergic patients and in health care workers who had been exposed to thimerosal-preserved vaccines. 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 against sensitization by these substances.


METHODS
To address this question, a case control study was conducted, including 91 Central European individuals with a positive patch-test reaction to thimerosal. This population was compared with 169 healthy controls and additionally with 114 individuals affected by an allergy against para-substituted aryl compounds. The latter population was included in order to test whether possible associations were due to substance-specific effects, or were a general feature connected with type IV immunological diseases. Homozygous deletions of GSTT1 and GSTM1 were determined by polymerase chain reaction.


RESULTS
Glutathione S-transferase M1 deficiency was significantly more frequent among patients sensitized to thimerosal (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 thimerosal-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. thimerosal 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.
Westphal
G A
GA
Abteilung für Arbeits- und Sozialmedizin, Georg-August-Universität Göttingen, Germany. gwestph@gwdg.de
Schnuch
A
A
Schulz
T G
TG
Reich
K
K
Aberer
W
W
Brasch
J
J
Koch
P
P
Wessbecher
R
R
Szliska
C
C
Bauer
A
A
Hallier
E
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004342:Drug Hypersensitivity / Q000276:immunology*; D005260:Female; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011310:Preservatives, Pharmaceutical / Q000009:adverse effects*; D013849:Thimerosal / Q000009:adverse effects* / Q000276:immunology
D011310:Preservatives, Pharmaceutical; D013849:Thimerosal; D005982:Glutathione Transferase