N-Acetyltransferase 2 polymorphism in patients with Spanish toxic oil syndrome. (Correspondence).

Ladona et al. (1) reported on the possible relationship between several genetic polymorphisms that regulate enzymatic activities involved in the processing of multiple xenobiotics and the risk of Spanish toxic oil syndrome (TOS). TOS, a disease that affected several thousand Spaniards 20 years ago, was attributed to the ingestion of adulterated rapeseed oil. Ladona et al. (1) reported an excess of N-acetyltransferase 2 (NAT2) slow-acetylation alleles and, consequently, an excess of slow acetylator genotypes in long-term survivors of this syndrome when they were compared to a group of "friends" (i.e., not consanguineous subjects living in the same area) but not when they were compared to siblings who were not affected by the syndrome.

In this setting, I find that the frequency of NAT[2.sup.*]4 (wild type) normal allele reported in the "friends" control group is exceedingly high (0.38) when compared to that found in previous studies in Spanish and in other Caucasian populations (2,3); the results in these studies are in concordance with the proportion of slow acetylator phenotypes found in the same populations (4,5). Could this difference be due to the small number of subjects included in the control groups studied by Ladona et al. (1)?

In contrast, if the differences between patients and controls were actually due to an excess of slow acetylators among patients, this could reflect that slow acetylation serves a protective role. These subjects are long-term survivors of the syndrome, and it is possible that rapid acetylators had a higher risk of dying in the acute phase of the disease.

In 1981 we used sulfamethazine as an enzyme-specific substrate (6) to determine the acetylator phenotype in 83 Spanish patients (36 males, age 46.8 [+ or -] 16.7 years, mean [+ or -] SD) suffering TOS in its acute phase and in 157 normal controls (7). All subjects were from the same geographic area (Madrid, Spain) and ethnic origin (white Spaniards) as those studied by Ladona et al. (1). Results of our study (7) are shown in Table 1. We found no differences in the distribution of both phenotypes between cases and controls, with almost identical frequencies for slow acetylator individuals in both subgroups. These frequencies are also consistent with those reported for the Spanish and other Caucasian populations (4,5).

Ladona et al. (1) reported that the frequency of the m2 allele (i.e., NAT[2.sup.*]6) in patients (0.32) was higher than that found in both control groups. Fretland et al. (8) have demonstrated that there are quantitative and qualitative differences in the metabolic activity of the enzymatic proteins coded by NAT2-mutated slow-acetylator alleles. Thus, it may be hypothetized that a selective affinity exists between any toxic component of rapeseed oil and any of the mutated slow-acetylator alleles.

Jose M. Ladero
Complutense University Medical School
Madrid, Spain
E-mail: [e-mail]
Table 1. Acetylator phenotype in patients with
toxic oil syndrome and in normal controls.

                     Slow              Rapid
Group (n)        acetylators (%)   acetylators (%)

Patients              55                45
Controls (157)        57                43

REFERENCES AND NOTES

(1.) Ladona MG, Izquierdo-Martinez M, Posada de la Paz M, de la Torre R, Ampurdanes C, Segura J, Sanz EJ. Pharmacogenetic profile of xenobiotic enzyme metabolism in survivors of the Spanish toxic oil syndrome. Environ Health Perspect 109:369-375 (2001).

(2.) Agundez JAG, Olivera M, Martinez C, Ladero JM, Benitez J. Identification and prevalence study of 17 allelic variants of the human NAT2 gene in a white population. Pharmacogenetics 6:423-428 (1996).

(3.) Meyer UA, Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol; 37:269-296 (1997).

(4.) Ladero JM, Arrojo A, Gilsanz V. Acetilacion hepatica en la poblacion espanola [in Spanish]. Gastroenterologia y Hepatologia 2:236-240 (1979).

(5.) Price-Evans DA. N-Acetyltransferase. In: Pharmacogenetics of Drug Metabolism (Kalow W, ed). New York:Pergamon Press, 1992;95-178.

(6.) Price-Evans DA. An improved and simplified method of detecting the acetylator phenotype. J Med Genet 6:405-407 (1969).

(7.) Ladero JM, Arrojo A. Envejecimiento y fenotipo acetilador hepatico [in Spanish]. Revista Iberamericana de Investigacion Clinica 2:21-26 (1983).

(8.) Fretland A, Leff MA, Doll MA, Hein DW. Functional characterization of human N-acetyltransferase 2 (NAT2) single nucleotide polymorphisms. Pharmacogenetics 11:207-215 (2001).