GSTM1 and XRCC3 polymorphisms: Effects on levels of aflatoxin B1-DNA adducts

Abstract

Objective: Aflatoxin B1 (AFB1), which can cause the formation of AFB1-DNA adducts, is a known human carcinogen. AFB1-exposure individuals with inherited susceptible carcinogen-metabolizing or repairing genotypes may experience an increased risk of genotoxicity. This study was designed to investigate whether the polymorphisms of two genes, the metabolic gene Glutathione S-transferase M1 (GSTM1) and DNA repair gene x-ray repair cross-complementing group 3 (XRCC3), can affect the levels of AFB1-DNA adducts in Guangxi Population (n= 966) from an AFB1-exposure area.Methods: AFB1-DNA adducts were measured by ELISA, and GSTM1 and XRCC3 codon 241 genotypes were identified by PCR-RFLP.Results: The GSTM1-null genotype [adjusted odds ratio (OR) = 2.09; 95% confidence interval (CI) = 1.61−2.71] and XRCC3 genotypes with 241 Met alleles [i.e., XRCC3-TM and -MM, adjusted ORs (95% CI) were 1.43 (1.08−1.89) and 2.42 (1.13−5.22), respectively] were significantly associated with higher levels of AFB1-DNA adducts. Compared with those individuals who did not express any putative risk genotypes as reference (OR = 1), individuals featuring all of the putative risk genotypes did experience a significantly higher DNA-adduct levels (adjusted ORs were 2.87 for GSTM1-null and XRCC3-TM; 5.83 for GSTM1-null and XRCC3-MM). Additionally, there was a positive joint effect between XRCC3 genotypes and long-term AFB1 exposure in the formation of AFB1-DNA adducts. Conclusion: These results suggest that individuals with susceptible genotypes GSTM1-null, XRCC3-TM, or XRCC3-MM may experience an increased risk of DNA damage elicited by AFB1 exposure.

Genetic Polymorphisms in DNA Repair Genes XRCC4 and XRCC5 and Aflatoxin B1–related Hepatocellular Carcinoma

“…3 Once ingested, this toxin is metabolized mainly by cytochrome P450 into the genotoxic metabolic aFB1-exo-8,9-epoxide (aFB1epoxide). [31][32][33] Xrcc4 and Xrcc5 are two important Dna repair genes involved in the nHeJ pathway. 3,21 in our study, aFB1 exposure status was associated with liver cancer.…”

Polymorphisms in the coding region of X-ray repair complementing group 4 and aflatoxin B1-related hepatocellular carcinoma

“…However, increasing epidemiological evidence has exhibited that although many people are exposed to the same risk factor, only a relatively small proportion of individuals with chronic AFB1 exposure develop HCC 23‐26. These results imply that an individual susceptibility related to genetic factors (e.g., DNA repair capacity) might be correlated with the carcinogenesis of HCC caused by chronic AFB1 exposure, whereas NHEJ genes play an important role in the repair of DSBs resulting from exogenous attacks, such as AFB1, and might be important cancer‐correlated genetic factors 27‐29…”

DNA Repair Capacity-Related to Genetic Polymorphisms of DNA Repair Genes and Aflatoxin B1-Related Hepatocellular Carcinoma Among Chinese Population

“…Additionally, AFB1 exposure also induces the formation of such oxidation DNA damage as 8-oxodeoxyguanosine (8-oxod G), a common endogenous DNA adduct (36)(37)(38). Although these DNA adducts are mainly produced in liver cells, they are also found in the peripheral blood white cells (39,40). Recent studies have shown that the levels of AFB1-DNA adduct of the peripheral blood white cells are positively and lineally correlated with that of liver cells, implying analysis of AFB1-DNA adducts in the peripheral blood white cells may substitute for the elucidation of tissular levels of adducts (39,41).…”

“…During the process of damage removed by aforementioned repair pathways, DNA repair genes play a central role, because their function determines DNA repair capacity (12). It has been shown that reduction in DNA repair capacity related to DNA repair genes is associated with increased risk of cancers (4,(39)(40)(41)(58)(59)(60)(61)(62). Thus, genetic polymorphisms in DNA repair genes which contribute to the variation in DNA repair capacity may be correlated with risk of developing cancers, including AFB1-related HCC.…”