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Original article
Effect of CYP3A4 genetic polymorphisms on the genotoxicity of 4,4′-methylene-bis(2-chloroaniline)-exposed workers
  1. Chung-Ching Wang1,
  2. Wei-Liang Chen1,
  3. Chia-Ni Hsiung2,
  4. Sheng-Ta Chiang1,
  5. Ying-Chuan Wang1,
  6. Ching-Hui Loh2,
  7. I-Shen Lin1,
  8. Hong-I Chen3,
  9. Saou-Hsing Liou4,5
  1. 1Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
  2. 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Armed Forces General Hospital, National Defense Medical Center, Taichung, Taiwan, Republic of China
  3. 3Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan, Republic of China
  4. 4Department of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China
  5. 5National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan, Republic of China
  1. Correspondence to Dr Saou-Hsing Liou, National Institute of Environmental Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan, Republic of China; shliou{at}nhri.org.tw

Abstract

Objectives 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).

Methods 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).

Results 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.

Conclusions 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.

  • 4,4'-methylene-bis(2-chloroaniline)
  • micronucleated cells
  • CYP3A4 polymorphism
  • micronucleus

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Footnotes

  • Correction notice This paper has been updated since it first published online. The author affiliation countries have been corrected to the Republic of China.

  • Contributors C-CW conceived and carried out experiments, analysed data and wrote the paper. W-LC conceived and carried out experiments, analysed data and help to revise the paper. C-NH carried out experiments, analysed data and revised the paper. S-TC carried out experiments and analysed data. Y-CW carried out experiments. C-HL carried out experiments. I-SL helped to draft the manuscript. H-IC conceived and carried out experiments. S-HL conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

  • Funding This study was partly supported by the National Health Research Institutes and partly supported by the National Science Council of the Republic of China (NSC95-2314-B-016-054).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval TSGHIRB approval number: 093-05-00085.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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