Effects of ALDH2, CYP1A1, and CYP2E1 genetic polymorphisms and smoking and drinking habits on toluene metabolism in humans.
In this study, we evaluated the effects of ALDH2, CYP1A1, and CYP2E1 genetic polymorphisms and smoking and drinking habits on the toluene metabolism. The study subjects were 92 male workers who handle toluene in a printing factory, an electrical parts factory, and a painting workplace in Japan. Their exposure levels to toluene were monitored using the diffusion-type sampler. Benzyl alcohol concentrations in their blood and hippuric acid (HA) and creatinine concentrations in their urine at the end of a workshift were determined. The genotype of ALDH2 was classified into the homozygous genotype of a normal ALDH2 gene (NN), the homozygous genotype of an inactive ALDH2 gene (DD), and the heterozygous genotype of normal and inactive ALDH2 genes (ND). The genetic polymorphism of CYP1A1 and CYP2E1 were also determined by restriction fragment length polymorphism (RFLP). A strong correlation between the personal exposure level and the urinary HA concentration was observed. Regression lines were calculated after being divided by the five factors, i.e., ALDH2, CYP1A1, CYP2E1, smoking, and drinking. The HA formation from toluene was significantly (p < 0.001) different among the genotypes of ALDH2. The slopes of the regression lines decreased from NN to ND to DD in this order. The benzyl alcohol concentration in the blood of the DD group was significantly higher than that found in the NN and ND groups. This result demonstrates that ALDH2 polymorphism affects the oxidation of benzyl alcohol to benzoic acid. The toluene metabolism was also affected by CYP1A1 polymorphism. The slope for the Ile/Ile (the predominant homozygous allele) group was significantly lower than that for the Ile/Val (the heterozygous allele) and Val/Val (the rare homozygous allele) group after correction for creatinine. A drinking habit significantly (p < 0.05) reduced urinary HA concentration in the NN group. A smoking habit also significantly (p < 0.05) reduced urinary uncorrected HA concentration in both the NN and ND groups. In a multiple regression analysis, ALDH2 and the drinking habit were significantly (p < 0.01) associated with HA excretion after toluene exposure with and without correction for creatinine, and the corrected HA concentration was also significantly (p < 0.01) increased in the Ile/Val and Val/Val group of CYP1A1. The smoking habit reduced the corrected HA concentration (p < 0.05); however, the polymorphism in the 5'-flanking region of CYP2E1 did not affect HA appearance in urine.
Kawamoto
T
T
Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu, Japan.
Koga
M
M
Murata
K
K
Matsuda
S
S
Kodama
Y
Y
D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D001483:Base Sequence; D019905:Benzyl Alcohol; D001592:Benzyl Alcohols / Q000097:blood; D003404:Creatinine / Q000652:urine; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006626:Hippurates / Q000652:urine; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016273:Occupational Exposure; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism; D012150:Polymorphism, Restriction Fragment Length; D012044:Regression Analysis; D012907:Smoking / Q000009:adverse effects; D014050:Toluene / Q000009:adverse effects / Q000378:metabolism*
D001592:Benzyl Alcohols; D006626:Hippurates; D014050:Toluene; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D000444:Aldehyde Dehydrogenase; C071207:1,2-dimethylhydrazine demethylase; D010089:Oxidoreductases, N-Demethylating; D019905:Benzyl Alcohol; C030514:hippuric acid