Effect of CYP3A4 genetic polymorphisms on the genotoxicity of 4,4'-methylene-bis(2-chloroaniline)-exposed workers.
We investigated the relationship between 4,4'-methylene-bis(2-chloroaniline) (MBOCA) exposure and micronucleus (MN) frequency, and how this association was affected by genetic polymorphism of the cytochrome P450 enzyme (CYP3A4).



We divided the study population into an exposed group (n=44 with total urine MBOCA ≥20 μg/g creatinine) and a control group (n=47 with total urine MBOCA <20 μg/g creatinine). Lymphocyte MN frequency (MNF) and micronucleated cell (MNC) frequency were measured by the cytokinesis-block MN assay method. MNF reported as the number of micronuclei in binucleated cells per 1000 cells, and MNC reported as the number of binucleated cells with the presence of MN per 1000 cells. CYP3A4 alleles were measured by PCR-based restriction fragment length polymorphism (PCR-RFLP).



The mean MNF (6.11 vs 4.46 MN/1000 cells, p<0.001) and MNC (5.75 vs 4.15 MN/1000 cells, p<0.001) in the exposed workers was significantly higher than that in the controls. The CYP3A4 polymorphism A/A+A/G influenced the difference in the mean MNF (5.97 vs 4.38 MN/1000 cells, p<0.001) and MNC (5.60 vs 4.15 MN/1000 cells, p<0.001) between the MBOCA-exposed and control groups. After adjusting risk factors, the MNF level in the MBOCA-exposed workers was 0.520 MN cells/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. Similarly, the MNC level in the MBOCA-exposed workers was 0.593 MN/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. However, the difference in adjusted MNF and MNC between the exposed and control groups was not significant for the CYP3A4 polymorphism with the G/G genotype.



We recommend that lymphocytes MNF and MNC are good indicators to evaluate MBOCA genotoxicity. Individuals with the CYP3A4 polymorphism A/A and A/G genotypes appear to be more susceptible to MBOCA genotoxicity.
Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Chung-Ching
CC
Wang
Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Wei-Liang
WL
Chen
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Armed Forces General Hospital, National Defense Medical Center, Taichung, Taiwan, Republic of China.
Chia-Ni
CN
Hsiung
Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Sheng-Ta
ST
Chiang
Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Ying-Chuan
YC
Wang
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Armed Forces General Hospital, National Defense Medical Center, Taichung, Taiwan, Republic of China.
Ching-Hui
CH
Loh
Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
I-Shen
IS
Lin
Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan, Republic of China.
Hong-I
HI
Chen
Department of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China.|National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan, Republic of China.
Saou-Hsing
SH
Liou
D000328:Adult; D000428:Alcohol Drinking / Q000453:epidemiology; D000704:Analysis of Variance; D000814:Aniline Compounds / Q000009:adverse effects* / Q000652:urine; D015992:Body Mass Index; D051544:Cytochrome P-450 CYP3A / Q000097:blood / Q000235:genetics* / Q000652:urine; D003577:Cytochrome P-450 Enzyme System; D005260:Female; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000737:chemistry; D008297:Male; D008753:Methylenebis(chloroaniline) / Q000009:adverse effects* / Q000032:analysis; D008875:Middle Aged; D009152:Mutagenicity Tests; D016273:Occupational Exposure / Q000009:adverse effects*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology; D013624:Taiwan / Q000453:epidemiology
D000814:Aniline Compounds; D008753:Methylenebis(chloroaniline); D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C025257:2-chloroaniline
4,4'-methylene-bis(2-chloroaniline); CYP3A4 polymorphism; micronucleated cells; micronucleus