Glutathione transferase activity and formation of macromolecular adducts in two cases of acute methyl bromide poisoning

Abstract

Objectives - To determine the activity of glutathione transferase and to measure the S-methylcysteine adducts in blood proteins, after acute inhalational exposure to methyl bromide. To examine the influence of the polymorphism of glutathione-S-transferase θ (GSTT1) on the neurotoxicity of methyl bromide. Methods - Two workers acutely exposed to methyl bromide with inadequate respiratory protective devices were poisoned. Seven weeks after-the accident, blood samples were drawn from both patients, for measurement of glutathione transferase activity in erythrocytes (conjugator status - that is, GSTT1 phenotype) and measurement of binding products of methyl bromide with blood proteins. Conjugator status was determined by a standard procedure. The binding product of methyl bromide, S-methylcysteine, was measured in globin and albumin. Results - Duration and intensity of exposure were identical for both patients as they worked together with the same protective devices and with similar physical effort. However, one patient had very severe poisoning, whereas the other only developed mild neurotoxic symptoms. The first patient was a 'conjugator' with normal glutathione transferase activity, whereas this activity was undetectable in the erythrocytes of the second patient, who consequently had higher concentrations of S-methylcysteine adduct in albumin (149 v 91 nmol/g protein) and in globin (77 v 30 nmol/g protein). Conclusions - Methyl bromide is genotoxic and neurotoxic. Its genotoxicity seems to be the consequence of the alkylating activity of the parent compound, and conjugation to glutathione has a protective effect. The data presented here suggest a different mechanism for methyl bromide neurotoxicity which could be related to the transformation of methylglutathione into toxic metabolites such as methanethiol and formaldehyde. If such metabolites are the ultimate toxic species, N-acetylcysteine treatment could have a toxifying rather than a detoxifying effect.