Polymorphism of xenobiotic-metabolizing enzymes and excretion of styrene-specific mercapturic acids

The role of polymorphic xenobiotic-metabolizing enzymes in the interindivid ual variability of phenylhydroxyethyl mercapturic acids (PHEMAs) was invest igated in 56 styrene-exposed workers. Ambient monitoring was carried out us ing passive personal samplers (geometric mean, 157 mg/m(3) 8-h time-weighte d average; geometric standard deviation, 2.90). Biomonitoring was based on mandelic acid and phenylglyoxylic acid in urine spot samples collected at t he end of the work shift ("end-of-shift") and prior to the subsequent shift ("next morning"). Four PHEMA diastereoisomers, namely (R,R)-M1, (SR)-M1, ( SR)-M2, and (RR)-M2, were determined by HPLC/tandem mass spectrometry. The genotypes of glutathione S-transferases M1-1 (GSTM1), T1-1 (GSTT1) and P14 (GSTP1), and microsomal epoxide hydrolase (EPHX) were characterized by PCR- based methods. Workers bearing the GSTM1pos genotype showed PHEMA concentra tions five and six times higher (in end-of-shift and next-morning samples, respectively) as compared to GSTM1null people. In GSTM1pos subjects, (RR)-M 1 was the main mercapturate affected by the GSTM1 status, accounting for 54 and 68% of total PHEMAs in end-of-shift and next-morning samples, respecti vely. Compared to GSTM1null, GSTM1pos subjects excreted more -M1 than -M2 a nd more (RR)-M1 and (SR)-M2 than (S,R)-M1 and (RR)-M2 diastereoisomers. Thu s, GSTM1-1 is the main isoenzyme catalyzing GSH-conjugation of styrene-7,8- oxide in humans and it seems to act in a regio- and stereoselective way. PH EMAs cannot be recommended as biomarkers of exposure to styrene, unless the GSTM1 genotype is considered in data interpretation. Their role as biomark ers of susceptibility deserves further studies.