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Influence of Metabolic Genotypes on Biomarkers of Exposure to 1,3-Butadiene in Humans¹

Dipartimento di Medicina del Lavoro, Istituti Clinici di Perfezionamento, Milano, Italy 20122 [S. F.]; Dipartimento di Medicina Interna e Medicina Pubblica, Università di Bari, Bari, Italy 70124 [L. S., L. V.]; Institute of Environmental Medicine, Karolinska Institutet and National Institute for Working Life, Stockholm, Sweden 17177 [M. W., A. R.]; Department of Toxicology, University of Würzburg, Würzburg, Germany 97078 [P. B., H-G. N.]; Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, North Carolina 27599 [P. B., J. A. S.]; and Dipartimento di Medicina del Lavoro, Università degli Studi di Milano, Milano, Italy 20122 [V. F., A. C.]

Carcinogenicity of 1,3-butadiene (BD) has been linked to its metabolic activation of genotoxic epoxides. The inherited variations in the activity of BD-metabolizing enzymes may be responsible for individual differences that modulate the effects of BD exposure. In this study, 40 Italian subjects (30 BD-exposed workers and 10 clerks) were investigated to evaluate the role of genetic polymorphism of cytochromes P450 2E1, microsomal epoxide hydrolase, glutathione transferases GSTM1, GSTP1, GSTT1, and alcohol dehydrogenase, on urinary N-acetyl-S-(3,4-hydroxybutyl)-L-cysteine (MI) and hemoglobin N-(2,3,4-trihydroxybutyl)-valine adducts (THBVal). Median urinary MI and THBVal levels were 1.71 mg/g creatinine and 37.0 pmol/g globin in BD-exposed workers (exposure range, 4–201 µg/m³) and 1.42 mg/g creatinine and 35.3 pmol/g globin in unexposed subjects. No difference between the two groups was observed. Among all subjects, MI and THBVal levels were significantly correlated (r = 0.333). Smoking positively influenced the formation of THBVal. Higher THBVal levels were found in subjects with GSTM1 null and GSTT1 null genotypes; borderline influences were also noticed for CYP2E1(G_-35T). An additive effect of combined polymorphisms for CYP2E1, GSTM1, and GSTT1 genes on the THBVal levels was suggested. A multiple linear regression analysis, where each factor contributed significantly, correlated THBVal levels with smoking, CYP2E1(G_-35T), GSTT1, and GSTM1 genotypes (r = 0.698). Our results indicate that the THBVal level is influenced by genotypes, and that the analysis of combined polymorphisms may be the key to a better understanding of the role played by polymorphism of BD-metabolizing enzymes.

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