Elsevier

The Lancet

Volume 363, Issue 9403, 10 January 2004, Pages 119-125
The Lancet

Mechanisms of Disease
Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study

https://doi.org/10.1016/S0140-6736(03)15262-2Get rights and content

Summary

Background

Particulate pollution is associated with the occurrence of asthma and allergy. The model pollutant, diesel exhaust particles, can participate with allergens in starting and exacerbating allergic airway diseases in part by production of reactive oxygen species. Glutathione-S-transferases (GSTs) can metabolise reactive oxygen species and detoxify xenobiotics present in diesel exhaust particles. We tested the hypothesis that null genotypes for gstm1 and gstt1, and gstp1 codon 105 variants (I105 and V105) are key regulators of the adjuvant effects of diesel exhaust particles on allergic responses.

Methods

Patients sensitive to the ragweed allergen were challenged intranasally with allergen alone and with allergen plus diesel exhaust particles in a randomised order at separate visits. Nasal allergen-specific IgE, histamine, interleukin 4, and interferon γ concentrations were measured before and 24 h after challenge.

Findings

Individuals with GSTM1 null or the GSTP1 I105 wildtype genotypes showed enhanced nasal allergic responses in the presence of diesel exhaust particles. Compared with patients with a functional GSTM1 genotype, GSTM1 null patients had a significantly larger increase in IgE (median 102·5 U/mL [range 1·0–510·5] vs 45·5 U/mL [1·5–60·6], p=0·03) and histamine (14·0 nmol/L [–0·2–24·7] vs 7·4 nmol/L [1·2–12·3], p=0·02) after diesel exhaust particles plus allergen challenge. The I105 GSTP1 genotype was associated with an increase in IgE (120·3 U/mL [6·7–510·5] vs 27·7 U/mL [–1·5–60·6], p=0·03) and histamine (13·8 nmol/L [3·1–24·7] vs 5·2nmol/L [–0·2–19·6], p=0·01) after challenge with diesel exhaust particles and allergens. The diesel exhaust particles enhancement was largest in patients with both the GSTM1 null and GSTP1 I/I genotypes.

Interpretation

GSTM1 and GSTP1 modify the adjuvant effect of diesel exhaust particles on allergic inflammation.

Introduction

Exposure to ambient air pollution is associated with many adverse health effects ranging from increased symptoms of allergic airway disease to increased mortality.1, 2, 3 Research has focused on the effects of ambient particulate pollution and much evidence indicates that particulate pollution is associated with the occurrence of asthma and allergy.4, 5, 6, 7, 8, 9

Understanding the effects of diesel exhaust particles on allergic airway diseases has been one focus of research on particulate pollution. Diesel exhaust contains small particles ranging from nanoparticles to coarse particles with mass concentrated in the accumulation mode centred at 0·2 μm in diameter that have high deposition rates in the lung and long residence times in the atmosphere.10 These primary diesel exhaust particles aggregate into a broad range of sizes and are important contributors to particular matter less than 10 μm in diameter (PM10) and particular matter less than 2·5 μm in diameter (PM2·5). Inhaled diesel exhaust particles can be deposited in the upper and lower respiratory tract and can participate with allergens in starting and exacerbating allergic diseases in the airway5, 6, 11, 12, 13, 14, 15, 16. In conjunction with allergen, diesel exhaust particles can act as an adjuvant to enhance IgE antibody responses, T-helper 2 (Th2) cytokine production, and histamine release in vivo. As with other inhaled pollutants, diesel exhaust particles are thought to exert major effects through production of reactive oxygen species. Antioxidants reduce the allergic inflammatory effects of diesel exhaust particles in vitro and in mice.9, 17, 18, 19 The role of antioxidants in allergic responses to diesel exhaust particles suggests that sensitivity to the effects of diesel exhaust particles is related to variation in antioxidant defences.

Several small molecules and proteins are involved in airway antioxidant defences that might mediate sensitivity to diesel exhaust particles.20 Glutathione-S-transferases (GSTs) are a large family of proteins that participate in antioxidant defences through several mechanisms including reactive oxygen species metabolism and detoxification of xenobiotics present in diesel exhaust particles. We focused on GSTM1, GSTT1, and GSTP1 genotypes because these genes are expressed in the respiratory tract, are involved in detoxification of chemicals present in diesel exhaust particles, and have common functional variant alleles.21 These variant alleles result in either total absence or a substantial change in enzyme activity. Furthermore, three members of this superfamily GSTM1, GSTT1, and GSTP1 with common genetic variants are thought to affect allergic airway disease and might explain variation in responses to diesel exhaust particles.22, 23, 24

To test the hypothesis that common genetic variants null genotypes for GSTM1 and GSTT1, and GSTP1 codon 105 variants (I105 and V05) affect susceptibility to diesel exhaust particles' enhancement of allergic responses, we used an established human nasal provocation model. Nasal allergic responses were measured after challenge with allergen and allergen plus diesel exhaust particles to determine whether functional variants in genes involved in antioxidant defences can account for the variation between individuals in their responses to diesel exhaust particles.

Section snippets

Participants

We recruited 19 non-smoking volunteers (seven males and 12 females) in Los Angeles, CA, USA. All had a positive epicutaneous skin test (>4 mm wheal with surrounding erythema) to short ragweed (an allergen not present in the Los Angeles region) and an allergy history consistent with allergic rhinitis. Based on interview responses, none of the volunteers had any atypical exposure to pollutants and no air pollution alerts in the Los Angeles area were reported during the study periods. None of the

Results

Table 1 shows the participants' characteristics. GSTM1 and GSTT1 null genotypes were present in 74% (14 of 19) and 47% (nine of 19) of patients, respectively. Most (68%, 13 of 19) patients were homozygous for the GSTP1 I105 wild-type allele and none was homozygous for the GSTP1 V105 variant allele. We selected the patients on the basis of their nasal allergy status, which probably explains the genotype distribution that differs from that seen in general population studies.

We have previously

Discussion

Our results show that susceptibility to an adverse health effect of diesel exhaust particles, a model oxidant pollutant, can be controlled by functional variation in natural antioxidant defenses. Several polymorphic genes including those for GSTs have been associated with atopy (allergy, asthma, and atopic dermatitis). Here, we provide evidence that the GSTM1 and GSTP1 genotypes play an important part in susceptibility to the adjuvant effects of oxidant pollutants such as diesel exhaust

GLOSSARY

diesel exhaust particles
Diesel exhaust particles are respirable particles produced during compression ignition of diesel fuel. The particles are composed of elemental and organic carbon compounds as well as trace amount of other elements with toxic properties including transition metals.
gstm1
Glutathione-S-transferases are involved in phase 2 xenobiotic and reactive oxygen species metabolism and have coordinate regulation based on antioxidant response element in their promoter region. GSTM1 is a

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