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-acetyltransferases (NATs) are enzymes involved in the detoxification of hazardous agents. The GSTM1 and GSTT1 genes exhibit null (i.e., deletion) polymorphisms; in specific individuals, homozygous deletion (i.e., both copies lost) of these genes can be detected. Polymorphism of the NAT2 gene results in slow and fast acetylators of potentially toxic substances. The GSTM1-null and the NAT2 slow-acetylator genotypes have been associated with increased risks for the development of environmentally induced cancers.


OBJECTIVE
We assessed whether homozygous GSTM1-null or GSTT1-null genotypes or the NAT2 slow-acetylator genotype were associated with increased risks for the development of malignant and nonmalignant asbestos-related pulmonary disorders in a cohort of Finnish construction workers.


METHODS
The study population consisted of 145 asbestos insulators who were classified as having been exposed to high levels of asbestos; 69 of these individuals had no pulmonary disorders (control subjects), and 76 had either malignant mesothelioma (n = 24) or nonmalignant pulmonary disorders, such as asbestosis and/or pleural plaques (n = 52). Lymphocyte DNA and the polymerase chain reaction were used to determine the GSTM1, GSTT1, and NAT2 genotypes of the study subjects. 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 were not affected significantly by homozygous deletion of the GSTM1 or GSTT1 genes. However, the risk of developing both malignant and nonmalignant 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 developing malignant mesothelioma for NAT2 slow acetylators was increased almost 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 approximately 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.


CONCLUSIONS
Individuals with homozygous deletion of the GSTM1 gene and a NAT2 slow-acetylator genotype who are exposed to high levels of asbestos appear to have enhanced susceptibility to asbestos-related pulmonary disorders.
Hirvonen
A
A
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
Saarikoski
S T
ST
Linnainmaa
K
K
Koskinen
K
K
Husgafvel-Pursiainen
K
K
Mattson
K
K
Vainio
H
H
D000107:Acetylation; D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001194:Asbestos / Q000009:adverse effects*; D015331:Cohort Studies; D015342:DNA Probes; D004198:Disease Susceptibility; D005387:Finland; D017353:Gene Deletion; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics; D008875:Middle Aged; D009784:Occupational Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*; D016273:Occupational Exposure / Q000009:adverse effects*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012306:Risk
D015342:DNA Probes; D001194:Asbestos; D001191:Arylamine N-Acetyltransferase; D005982:Glutathione Transferase