Concentrations of ochratoxin A in the urine of endemic nephropathy patients and controls in Bulgaria: lack of detection of 4-hydroxyochratoxin A.

Ochratoxin A has been detected more frequently and at higher levels as a contaminant in staple food consumed by subjects affected by Balkan endemic nephropathy or urinary tract tumours in the Vratza district (Bulgaria) than in samples from control populations in and outside the endemic area. Serum from patients with Balkan endemic nephropathy also contained ochratoxin A more frequently and at higher levels than serum from controls. Metabolic phenotyping of subjects in the Vratza district with debrisoquine revealed a preponderance of extensive metabolizers among subjects at high risk for Balkan endemic nephropathy. In rats, ochratoxin A is metabolized to 4-hydroxyochratoxin A, and rat strains shown to be poor or extensive metabolizers of debrisoquine were also poor or extensive metabolizers of ochratoxin A. In order to determine whether the metabolic phenotype for debrisoquine also parallels that of ochratoxin A in humans, a sensitive method was developed for quantifying ochratoxin A and its 4-hydroxy metabolite in human urine. This method was subsequently used to analyse urine from subjects who had previously been phenotyped for debrisoquine. Ochratoxin A was detected more frequently and at higher levels in urine from members of families affected by Balkan endemic nephropathy than in samples taken from subjects in control areas. No 4-hydroxyochratoxin A was found in any of these samples (detection limit, 15 ng/l urine). On the basis of results from human studies and animal models, the role of genetic polymorphism in drug oxidation and disease susceptibility is discussed briefly.