Genetic polymorphisms influence variability in benzene metabolism in humans

The role of genetic polymorphism in modulating urinary excretion of two ben zene metabolites, i.e. trans,trans-muconic acid (t,t-MA) and S-phenylmercap turic acid (PMA), has been investigated in 59 non-smoking city bus drivers, professionally exposed to benzene ria vehicle exhausts, Exposure to benzen e was determined by personal passive samplers (mean +/- SD = 82.2 +/- 25.6 mu g/m(3)). while internal dose and metabolic rate were evaluated by measur ing urinary excretion of unmodified benzene (mean +/- SD = 361 +/- 246 ng/l ), t,t-MA (mean +/- SD = 602 +/- 625 mu g/g creatinine), and PMA (mean +/- SD = 5.88 +/- 4.76 mu g/g creatinine). Genetic polymorphism at six loci enc oding cytochrome-P450-dependent monooxygenases (CYP2E1 and CYP2D6), glutath ione-S-transferases (GSTT1, GSTP1 and GSTM1) and NAD(P)H:quinone oxidoreduc tase (NQOR) was determined by polymerase chain reaction-based methods. No e vidence emerged for a possible role of CYP2E1, GSTM1 and GSTP1 polymorphism s in determining the wide differences observed in the rate of benzene biotr ansformation, Conversely a significantly higher t,t-MA urinary excretion wa s found to be correlated to GSTT1 null genotype, and a significantly lower PMA excretion was detected in the subjects lacking NQOR activity and in the CYP2D6 extensive-metabolizers. Many biological (i.e. age and body burden) or lifestyle factors (i.e. rural or urban residence, use of paints and solv ents, medication, alcohol and coffee intake), also taken into account as po tential confounders, did not influence the correlations found. These findin gs suggest that CYP2D6, GSTT1 and NQOR polymorphisms contribute in explaini ng the metabolic variability observed in our sample. Therefore, these polym orphisms should be regarded as potential risk factors for benzene-induced a dverse health effects. Pharmacogenetics 9:445-451 (C) 1999 Lippincott Willi ams & Wilkins.