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Cross-Talk Between One-Carbon Metabolism and Xenobiotic Metabolism: Implications on Oxidative DNA Damage and Susceptibility to Breast Cancer

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Abstract

The aim of this case–control study is to explore the role of aberrations in xenobiotic metabolism in inducing oxidative DNA damage and altering the susceptibility to breast cancer. Cytochrome P4501A1 (CYP1A1) m1 (OR: 1.41, 95% CI 1.08–1.84), CYP1A1 m4 (OR: 5.13, 95% CI 2.68–9.81), Catecholamine-O-methyl transferase (COMT) H108L (OR: 1.49, 95% CI 1.16–1.92), and glutathione S-transferase (GST) T1 null (OR: 1.68, 95% CI 1.09–2.59) variants showed association with breast cancer risk. Reduced folate carrier 1 (RFC1) 80A/CYP1A1 m1/CYP1A1 m4 and RFC1 80A/thymidylate synthase (TYMS) 5′-UTR 2R/methionine synthase (MTR) 2756G/COMT 108L genetic combinations were found to inflate breast cancer risk under the conditions of low dietary folate (345 ± 110 vs. 379 ± 139 μg/day) and low plasma folate (6.81 ± 1.25 vs. 7.09 ± 1.26 ng/ml) by increasing plasma 8-oxo-2′-deoxyguanosine (8-oxodG). This increase in 8-oxodG is attributed to low methionine (49.38 ± 23.74 vs. 53.90 ± 23.85 μmol/l); low glutathione (378 ± 242 vs. 501 ± 126 μmol/l) and GSTT1 null variant; and hypermethylation of CpG island of extracellular-superoxide dismutase (EC-SOD) (92.78 ± 11.49 vs. 80.45 ± 9.86%), which impair O-methylation of catechol estrogens to methoxy estrogens, conjugation of glutathione to semiquinones/quinones and free radical scavenging respectively. Our results suggest cross-talk between one-carbon metabolism and xenobiotic metabolism influencing oxidative DNA damage and susceptibility to breast cancer.

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Acknowledgments

This study was supported by the grant funded by Indian Council of Medical Research (ICMR), New Delhi (Ref No. 5/13/32/2007). Dr. V.K. Kutala is recipient of Ramanujan Fellowship awarded by Department of Science & Technology (DST), Government of India. We thank Dr. Annie Q Hasan, Head, Department of Molecular Medicine, Kamineni Hospitals, Hyderabad for critical revision of the manuscript in terms of genetic aspects.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Nizam’s Institute of Medical Sciences, Panjagutta, Hyderabad, 500082, Andhra Pradesh, India

    Shaik Mohammad Naushad, Cheruku Apoorva Reddy, Yedluri Rupasree, Addepalli Pavani & Vijay Kumar Kutala

  2. Department of Medical Oncology, Nizam’s Institute of Medical Sciences, Panjagutta, Hyderabad, 500082, India

    Raghunadha Rao Digumarti

  3. Department of Surgical Oncology, Nizam’s Institute of Medical Sciences, Panjagutta, Hyderabad, 500082, India

    Suryanarayana Raju Gottumukkala

  4. Department of Internal Medicine, Ohio State University, Columbus, OH, 43210, USA

    Periannan Kuppusamy

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  1. Shaik Mohammad Naushad
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Correspondence to Vijay Kumar Kutala.

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Naushad, S.M., Reddy, C.A., Rupasree, Y. et al. Cross-Talk Between One-Carbon Metabolism and Xenobiotic Metabolism: Implications on Oxidative DNA Damage and Susceptibility to Breast Cancer. Cell Biochem Biophys 61, 715–723 (2011). https://doi.org/10.1007/s12013-011-9245-x

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