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Margarita G. Ladona,¹ Maravillas Izquierdo-Martinez,² Manuel Posada de la Paz,³ Rafael de la Torre,¹ Coral Ampurdanés,^1,4 Jordi Segura,¹ and Emilio J. Sanz⁵

¹Department of Pharmacology, Municipal Institute of Medical Investigation, Barcelona, Spain; ²Department of Internal Medicine, Hospital 12 de Octubre, Madrid, Spain; ³Centro de Investigación sobre el Aceite Tóxico, Instituto de Salud Carlos III, Madrid, Spain; ⁴Centro de Investigación y Desarrollo, CID-CSIC, Barcelona, Spain; ⁵Department of Pharmacology, La Laguna University, Tenerife, Spain

Abstract

In 1981, the Spanish toxic oil syndrome (TOS) affected more than 20,000 people, and over 300 deaths were registered. Assessment of genetic polymorphisms on xenobiotic metabolism would indicate the potential metabolic capacity of the victims at the time of the disaster. Thus, impaired metabolic pathways may have contributed to the clearance of the toxicant(s) leading to a low detoxification or accumulation of toxic metabolites contributing to the disease. We conducted a matched case-control study using 72 cases (54 females, 18 males) registered in the Official Census of Affected Patients maintained by the Spanish government. Controls were nonaffected siblings (n =72) living in the same household in 1981 and nonaffected nonrelatives (n = 70) living in the neighborhood at that time, with no ties to TOS. Genotype analyses were performed to assess the metabolic capacity of phase I [cytochrome P450 1A1 (CYP1A1) , CYP2D6] and phase II [arylamine N-acetyltransferase-2 (NAT2) , GSTM1 (glutathione S-transferase M1) and GSTT1] enzyme polymorphisms. The degree of association of the five metabolic pathways was estimated by calculating their odds ratios (ORs) using conditional logistic regression analysis. In the final model, cases compared with siblings (72 pairs) showed no differences either in CYP2D6 or CYP1A1 polymorphisms, or in conjugation enzyme polymorphisms, whereas cases compared with the unrelated controls (70 pairs) showed an increase in NAT2 defective alleles [OR = 6.96, 95% confidence interval (CI) , 1.46-33.20] adjusted by age and sex. Glutathione transferase genetic polymorphisms (GSTM1, GSTT1) showed no association with cases compared with their siblings or unrelated controls. These findings suggest a possible role of impaired acetylation mediating susceptibility in TOS. Key words: CYP1A1, CYP2D6, enzyme genetic polymorphisms, GSTM1, GSTT1, molecular epidemiology, NAT2, Spanish toxic oil syndrome, xenobiotic metabolism. Environ Health Perspect 109:369-375 (2001) . [Online 16 March 2001]

http://ehpnet1.niehs.nih.gov/docs/2001/109p369-375ladona/ abstract.html

Address correspondence to M.G. Ladona, Centro de Investigación y Desarrollo, CID-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain. Telephone: +34 93-400 6100 ext. 337, 287. Fax: +34 93-204 5904. E-mail: mglqob@cid.csic.es

We thank the local Associations of TOS-Affected Patients for their help in patient recruitment and sample collection, and all patients participating in the study. We are also grateful to B. Terracini for helpful discussions and C. O'Hara for English revision of the manuscript.

The study was supported by grants 94/1828-1829 from the Fondo de Investigación Sanitaria (Spain) . The present study generated a patient DNA collection deposited in the CISAT Center (Madrid) , Centro de Investigación Sobre el Síndrome del Aceite de Colza.

Received 22 August 2000 ; accepted 14 November 2000.