CYP1A1 and GSTM1 polymorphisms affect urinary 1-hydroxypyrene levels after PAH exposure.
Certain human biotransformation enzymes have been implicated in the formation and scavenging of the ultimate reactive metabolites, the diolepoxides, from polycyclic aromatic hydrocarbons (PAHs). In the present study, performed on aluminum smelter workers, we have analyzed airborne PAH, the pyrene metabolite 1-hydroxypyrene (1-OHP) in urine, and genotypes for biotransformation enzymes involved in PAH metabolism. The aim was to evaluate the correlation between external exposure and biomarkers of exposure and to investigate to what extent genetic polymorphism in metabolic enzymes can explain interindividual variation in urinary 1-OHP levels. DNA was prepared from blood samples from 98 potroom workers and 55 controls and altogether eight polymorphisms in the CYP1A1, mEH, GSTM1, GSTP1 and GSTT1 genes were analyzed. The 1-OHP excretion was found to correlate significantly (P </= 0.005) to the exposure. The interindividual difference in excretion of 1-OHP was vast (>100-fold) and univariate and multivariate regression analyses were used to find the variables that could determine differences in excretion. The variation could, to some degree, be explained by differences in exposure to airborne particulate-associated PAHs, the use of personal respiratory protection devices, smoking habits and genetic polymorphisms in the cytochrome P450 1A1, GSTM1 and GSTT1 enzymes. The part of the variance that could be explained by differences in biotransformation genotypes seemed to be of the same order of magnitude as the variance explained by differences in exposure. In the control group as well as in the occupationally exposed group, the highest 1-OHP levels were observed in individuals carrying the CYP1A1 Ile/Val genotype who were also of the GSTM1 null genotype. The results show that urinary 1-OHP is a sensitive indicator of recent human exposure to PAHs and that it may also to some extent reflect the interindividual variation in susceptibility to PAHs.
Alexandrie
A K
AK
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Warholm
M
M
Carstensen
U
U
Axmon
A
A
Hagmar
L
L
Levin
J O
JO
Ostman
C
C
Rannug
A
A
D000535:Aluminum; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D016273:Occupational Exposure; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D011110:Polymorphism, Genetic; D011721:Pyrenes / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects
D007527:Isoenzymes; D011084:Polycyclic Aromatic Hydrocarbons; D011721:Pyrenes; D000535:Aluminum; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; C033146:1-hydroxypyrene