Genotoxic effect of N-hydroxy-4-acetylaminobiphenyl on human DNA: implications in bladder cancer.

Abstract

BACKGROUND:

The interaction of environmental chemicals and their metabolites with biological macromolecules can result in cytotoxic and genotoxic effects. 4-Aminobiphenyl (4-ABP) and several other related arylamines have been shown to be causally involved in the induction of human urinary bladder cancers. The genotoxic and the carcinogenic effects of 4-ABP are exhibited only when it is metabolically converted to a reactive electrophile, the aryl nitrenium ions, which subsequently binds to DNA and induce lesions. Although several studies have reported the formation of 4-ABP-DNA adducts, no extensive work has been done to investigate the immunogenicity of 4-ABP-modified DNA and its possible involvement in the generation of antibodies in bladder cancer patients.

METHODOLOGY/PRINCIPAL FINDINGS:

Human DNA was modified by N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP), a reactive metabolite of 4-ABP. Structural perturbations in the N-OH-AABP modified DNA were assessed by ultraviolet, fluorescence, and circular dichroic spectroscopy as well as by agarose gel electrophoresis. Genotoxicity of N-OH-AABP modified DNA was ascertained by comet assay. High performance liquid chromatography (HPLC) analysis of native and modified DNA samples confirmed the formation of N-(deoxyguanosine-8-yl)-4-aminobiphenyl (dG-C8-4ABP) in the N-OH-AABP damaged DNA. The experimentally induced antibodies against N-OH-AABP-modified DNA exhibited much better recognition of the DNA isolated from bladder cancer patients as compared to the DNA obtained from healthy individuals in competitive binding ELISA.

CONCLUSIONS/SIGNIFICANCE:

This work shows epitope sharing between the DNA isolated from bladder cancer patients and the N-OH-AABP-modified DNA implicating the role of 4-ABP metabolites in the DNA damage and neo-antigenic epitope generation that could lead to the induction of antibodies in bladder cancer patients.

• Authors: Uzma Shahab, Moinuddin, Saheem Ahmad, Kiran Dixit, Safia Habib, Khursheed Alam, Asif Ali
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e53205 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23382838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminobiphenyl Compounds
• Antibodies, Antinuclear
• Carcinogens
• DNA Adducts
• N-hydroxy-4-acetylaminobiphenyl
• DNA

Topics

• Aminobiphenyl Compounds (toxicity)
• Antibodies, Antinuclear (chemistry, immunology)
• Carcinogens (toxicity)
• Chromatography, High Pressure Liquid
• DNA (chemistry, drug effects)
• DNA Adducts (chemistry, immunology)
• Female
• Humans
• Nucleic Acid Conformation (drug effects)
• Placenta (chemistry, drug effects)
• Pregnancy
• Urinary Bladder Neoplasms (chemically induced, immunology, pathology)