Glutathione Genotype Affects Xenobiotic Enhancement of Allergic Responses

Frank D. Gilliland, Ph.D. and David Diaz-Sanchez, Ph.D.
University of Southern California
P01ES09581 and P30ES07048

Background: Among the health effects associated with particulate matter air pollution is the occurrence of asthma and allergy. Diesel exhaust particles can combine with allergens to cause or exacerbate allergic airways diseases in part by the production of reactive oxygen compounds. The enzyme glutathione-s-transferase is known to metabolize reactive oxygen compounds and to detoxify xenobiotics such as those present in diesel exhaust. These investigators tested the hypothesis that glutathione genotypes were key determinants in the severity of effects of diesel exhaust particles on allergic response.

Advance: Patients with ragweed sensitivity were challenged intranasally with ragweed pollen alone or in combination with diesel exhaust particles randomly on separate visits. Several markers for allergic response were measured before and 24 hours after challenge. Individuals with M1 null or P1 genotypes of the enzyme showed enhanced nasal allergic responses in the presence of diesel exhaust particles. Patients with the M1 null genotype had about twice the IgE and histamine responses observed in patients with functional M1 genotypes. The diesel exhaust particle enhancement was largest in patients with both the M1 null and P1 I/I genotypes.

Implication: These experiments indicate that glutathione genotype does indeed modify the effect of diesel exhaust particles on allergic inflammation. The investigators provide evidence that the M1 and P1 genotypes play an important part in susceptibility to the combined effects of oxidant pollutants such as diesel exhaust particles. They conclude that "[t]he importance of these results is heightened by the high frequency of polymorphisms of these genes in most populations. These results, therefore, have obvious clinical and public-health relevance especially for sensitized individuals living in urban environments."

Citation: Gilliland FD, Li YF, Saxon A, Diaz-Sanchez D. Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study. Lancet. 2004 Jan 10;363(9403):119-25.