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

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.

Effect of Tumour Necrosis Factor-Alpha on Estrogen Metabolic Pathways in Breast Cancer Cells

“…Formation of these adducts and the concomitant apurinic sites in DNA have been shown to induce mutations that are associated with initiation of breast cancer 49, 50. Indeed, our study demonstrated that treatment with TNF-α is associated with a significant increase in estrogen-induced depurinating adducts especially the Adenine adducts.…”

Association of COMT Val158Met polymorphism and breast cancer risk: an updated meta-analysis

“…Ten of these articles were excluded: one of these articles was a review [21], four were overlapped subjects [22-25], four did not provide allele or genotyping data [26-29], and one was a study concerned with COMT 1222 G>A polymorphism [30]. Manual search of references cited in the published studies did not reveal any additional articles.…”

Paradoxical role of C1561T glutamate carboxypeptidase II (GCPII) genetic polymorphism in altering disease susceptibility

“…Any perturbation in FGCP activity might result in low plasma folate levels in non-supplement users, thus leading to alterations in one-carbon homeostasis. As onecarbon metabolism plays a pivotal role in the synthesis, repair and methylation of DNA; any perturbation in this pathway may lead to an increased DNA damage, impaired remethylation of homocysteine, and aberrant DNA methylation (Naushad et al, 2011b;Smithells et al, 1976;Steegers-Theunissen et al, 1994;Vijaya Lakshmi et al, 2011). These changes are often associated with the cancer (Naushad et al, 2011b), CAD (Vijaya Lakshmi et al, 2011) and neural tube defects (Smithells et al, 1976;Steegers-Theunissen et al, 1994).…”