Pharmacogenetic Profile of Xenobiotic Enzyme Metabolism in Survivors of the Spanish Toxic Oil Syndrome

Abstract

Among food-related toxic outbreaks that have occurred in the world, the Spanish toxic oil syndrome (TOS) emerges as a significant disaster because of the degree of severity and the huge population involved (1,2). In May 1981 the TOS appeared in Madrid and northwestern areas of Spain as a unique disease caused by the ingestion of adulterated rapeseed oil denatured with aniline (3-7). More than 20,000 people were affected; of these, over 11,000 required hospitalization and over 300 deaths were registered in the first 2 years (1,8). Although the majority of patients recovered after a long period, 30-40% continue to suffer mild symptoms or severe sequelae (9-12). TOS was characterized as a multisystemic disease with three consecutive phases. In the acute phase (1-2 months), patients presented fever, rash, eosinophilia, pulmonary edema, and myalgia. Many patients (59%) progressed to an intermediate phase with pulmonary hypertension, thromboembolism, persistent myalgia and eosinophilia, skin edema, alopecia, and sicca syndrome. The clinical signs of the chronic phase were principally pulmonary hypertension, scleroderma, peripheral neuropathy, and liver disease.

Metabolism of (R)- and (S)-3-(Phenylamino)propane-1,2-diol in C57BL/6- and A/J-Strain Mice. Identification of New Metabolites with Potential Toxicological Significance to the Toxic Oil Syndrome

“…These findings have potential toxicological implications for TOS since patients could have had an enzyme activity impairment on pathways dealing with detoxification of PAP derivatives, resulting in the accumulation of reactive, unstable species similar to those reported here. In this respect, we recently reported that TOS survivors presented a specific profile derived from genetic polymorphisms on xenobiotic metabolism enzymes; in fact, impaired NAT-2 (acetylation) may have mediated susceptibility in those patients compared with their geographical controls (16). Moreover, reactive metabolites derived from xenobiotic metabolism have been associated with autoimmune diseases related to xenobiotic exposure (35,36), with immune activation being a crucial characteristic for TOS and EMS (37).…”

“…The latter acetanilide product can be metabolized to yield 4-aminophenol and paracetamol (34). Thus, a metabolic interaction between OLA and PAP derivatives could be postulated, and the metabolic findings (16) observed in TOS survivors (impaired acetylation) would have toxicological significance. Therefore, A/J and C57BL/6 mice could be considered good candidates for TOS-animal models, and our studies add a further step to determine the toxicokinetics necessary for future research seeking toxicity targets of these potentially toxic metabolites.…”

“…Therefore, our research line focused on investigating the metabolic profile of TOS patients in parallel with determining PAP derivative metabolism and distribution in mouse strains, and, further, applying the acquired knowledge to obtain an animal model for in-depth analysis of TOS pathogenic mechanisms. In this respect, we recently reported that TOS survivors exhibit a specific metabolic profile determined by molecular analyses on genetic polymorphisms of enzyme metabolism (16). In addition, we have studied the biotransformation and clearance of racemic PAP (rac-PAP) in the C57BL/6 and A/J mouse strains (17), a well-known murine model for human acetylation polymorphism.…”

In Vitro Bioactivation of 3-(N-Phenylamino)propane-1,2-diol by Human and Rat Liver Microsomes and Recombinant P450 Enzymes. Implications for Toxic Oil Syndrome

“…Ladona et al assessed genetic polymorphisms related to xenobiotic metabolism among TOS patients. They found that related patients had higher levels of arylamine N-acetyltransferase-2 (NAT2) than did unrelated patients, which suggested a correlation between impaired acetylation and susceptibility to intoxication by the oil (12).…”