GLUTATHIONE-S-TRANSFERASE AND N-ACETYLTRANSFERASE GENOTYPES AND ASBESTOS-ASSOCIATED PULMONARY DISORDERS

Background: Humans vary in their ability to metabolize endogenous and exogenous compounds. Glutathione S-transferases (GSTs) and N-acetyltra nsferases (NATs) are enzymes involved in the detoxification of hazardo us agents. The GSTM1 and GSTT1 genes exhibit null (i.e., deletion) pol ymorphisms; in specific individuals, homozygous deletion (i.e., both c opies lost) of these genes can be detected. Polymorphism of the NAT2 g ene results in slow and fast acetylators of potentially toxic substanc es, The GSTM1-null and the NAT2 slow-acetylator genotypes have been as sociated with increased risks for the development of environmentally i nduced cancers. Purpose: We assessed whether homozygous GSTM1-null or GSTT1-null genotypes or the NAT2 slow-acetylator genotype were associa ted with increased risks for the development of malignant and nonmalig nant asbestos-related pulmonary disorders in a cohort of Finnish const ruction workers. Methods: The study population consisted of 145 asbest os insulators who were classified as having been exposed to high level s of asbestos; 69 of these individuals had no pulmonary disorders (con trol subjects), and 76 had either malignant mesothelioma (n = 24) or n onmalignant pulmonary disorders, such as asbestosis and/or pleural pla ques (n = 52), Lymphocyte DNA and the polymerase chain reaction were u sed to determine the GSTM1, GSTT1, and NAT2 genotypes of the study sub jects. Odds ratios (ORs) and 95% confidence intervals (CIs) estimating the relative risks of disease associated with specific genotypes were calculated from 2 x 2 tables by use of Fisher's exact method, Results : Risks for the development of asbestos-related pulmonary disorders we re not affected significantly by homozygous deletion of the GSTM1 or G STT1 genes. However, the risk of developing both malignant and nonmali gnant pulmonary disorders for individuals with a NAT2 slow-acetylator genotype was more than twice that observed for those with a NAT2 fast- acetylator genotype (OR = 2.3; 95% CI = 1.1-4.7); the risk of developi ng malignant mesothelioma for NAT2 slow acetylators was increased almo st fourfold (OR = 3.8; 95% CI = 1.2-14.3). Individuals who lacked the GSTM1 gene and possessed a NAT2 slow-acetylator genotype had a risk of developing malignant and nonmalignant pulmonary disorders that was ap proximately fivefold greater than that observed for those who had the GSTM1 gene and a NAT2 fast-acetylator genotype (OR = 5.1; 95% CI = 1.6 -17.6); these individuals had a fourfold increased risk of developing nonmalignant pulmonary disorders (OR = 4.1; 95% CI = 1.1-17.2) and an eightfold increased risk of developing malignant mesothelioma (OR = 7. 8; 95% CI = 1.4-78.7) when compared with the same reference group. Con clusions: Individuals with homozygous deletion of the GSTM1 gene and a NAT2 slow-acetylator genotype who are exposed to high levels of asbes tos appear to have enhanced susceptibility to asbestos-related pulmona ry disorders.