Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects

Abstract

Gene-environment interactions play an important role in folate metabolism, with a potential impact on human health. Deficiencies in the uptake of key micronutrients and variant genotypes can affect the folic acid cycle, modulating methyl group transfer in key processes and leading to increased cancer risk and Down syndrome incidence. So far, the significance of folate status and metabolic genotypes on baseline levels of DNA damage in normal individuals has not been fully elucidated. In this study, the possible modulation of SCE, micronuclei and tail moment values in peripheral lymphocytes by plasma levels of folic acid, homocysteine and vitamin B12, and by the methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms was investigated in 191 healthy subjects. The results obtained show a highly significant (P = 0.001) positive association between plasma levels of vitamin B12 and frequencies of both SCE and high frequency cells (HFC, above 90 degrees percentile) in smokers. No significant effect was observed in non-smokers. Moreover, after correction for age, gender and GSTM1 genotype, a significant association (P = 0.026) between the MTRR 66GG variant genotype and higher micronucleus rates was observed. Tail moment values were not affected by any of the independent variables considered. Overall, the results obtained suggest that both folate status and relevant metabolic genotype can influence background levels of DNA damage in normal subjects. The significant association observed in smokers between plasma vitamin B12 and SCE frequencies may highlight the effect of methylation status on DNA damage and repair, although the role of other, unidentified dietary factors cannot be ruled out. At the same time, micronucleus data indicate that the MTRR 66GG variant may represent another individual trait of relative genomic instability, thus supporting epidemiological data on increased risk of Down syndrome conception in MTRR 66GG subjects.

Association between methionine synthase reductase A66G polymorphism and primary infertility in Chinese males

“…The SNP of each enzyme may affect enzyme activity to varying degrees by influencing the three-dimensional structure and amino acid substitution. Previous studies showed that the MTRR 66GG genotype contributed more than the MTHFR 677TT and MS 2756GG genotypes to the regulation of homocysteine levels (Gaughan et al, 2001;Jacques et al, 2003;Zijno et al, 2003). Our findings are partly consistent with these results.…”

Vitamin B12 Reduces Ribavirin-Induced Genotoxicity in Phytohemaglutinin-Stimulated Human Lymphocytes

“…This finding is in accordance with the study of Fenech et al (1998), who reported that the frequency of micronucleated cells correlate negatively with serum B12. Further studies of (Fenech 1999(Fenech , 2001Zijno et al 2003) demonstrated that micronuclei correlate positively with serum homocysteine levels and that the biochemical effects of folate and vitamin B12 deficiency are quite similar and include a functional folate deficiency (Narin et al 2002). Interplay between folate, vitamin B12 and homocysteine is important for the broad spectrum of biological effects, and certainly could influence or modulate genotoxicity.…”

“…Since vitamin B12 plays a significant role in numerous biological processes, we examined the potential beneficial effect of vitamin B12 supplementation on ribavirin-induced genotoxicity. Vitamin B12 acts as a coenzyme of methionine synthase which is required for the metabolism of folate and biosynthesis of nucleotides (Zijno et al 2003). The stability of the DNA is strongly influenced by vitamin B12 through its association with the folate metabolic pathway and nucleotide biosynthesis.…”

Polymorphisms ofMethionine SynthaseandMethionine Synthase Reductaseand Risk of Squamous Cell Carcinoma of the Head and Neck: a Case-Control Analysis

“…Indeed, our data showed that the SCCHN risk was significantly increased in a doseresponse manner as the number of the risk alleles increased, suggesting that the risk alleles of MTR A2756G and MTRR G66A may have a joint effect in increasing SCCHN risk. Because the interactions among folate-related genes, folate, and related dietary factors in tumorigenesis are complex (12,32), this possible gene-gene interaction and the mechanisms under which these polymorphisms affect risk of SCCHN warrant further investigations.…”