Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in The Gambia, West Africa

Wojnowski, Leszek; Turner, Paul C.; Pedersen, Bonnie R.; Hustert, Elisabeth; Brockmöller, Jürgen; Mendy, Maimuna; Whittle, Hilton; Kirk, Greg; Wild, Christopher P.

doi:10.1097/00008571-200410000-00007

Cited by 60 publications

(31 citation statements)

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“…The functional CYP3A5 variant allele, CYP3A5*1 is the most frequent variant allele in the black population (B50%) 8,13,16 , whereas in Ethiopians, the defective variant allele (CYP3A5*3) is the most frequent allele (67%). The lower frequency of CYP3A5*1 and absence of the black population-specific allele, CYP3A5*7, differentiate Ethiopians from other black Africans and African Americans with respect to CYP3A5 allele frequency distribution.…”

Section: Discussionmentioning

confidence: 99%

“…Few studies have investigated the genetic polymorphisms in CYP3A5 in African populations. 8,13,16 However, data from these studies cannot be extrapolated to other populations in the continent because Africans are heterogeneous with respect to pharmacogenetics of drug-metabolizing enzymes. 17,18 This study aimed at investigating the influence of CYP3A5 genotype and sex on the CYP3A phenotype and compared the use of plasma 4b-hydroxycholesterol and omeprazole to omeprazole sulfone ratio as CYP3A markers.…”

Section: Introductionmentioning

confidence: 99%

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Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

et al. 2010

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The objectives of the this study were to assess the influence of CYP3A5 genotype and sex on the variability in total CYP3A activity and to compare 4b-hydroxycholesterol and omeprazole sulfoxidation as phenotypic markers for CYP3A activity in Ethiopians. Healthy subjects (n ¼ 150) were genotyped for CYP3A5*3, *6 and *7 using allele-specific PCR and Taqman genotyping assays. Plasma levels of 4b-hydroxycholesterol, 3 h post-dose omeprazole and omeprazole sulfone, were determined by gas chromatography-mass spectrometry and high performance liquid chromatography, respectively. The frequency of CYP3A5*1, *3, *6 and *7 was 20.5, 67.3, 12.2 and 0%, respectively. The mean plasma 4b-hydroxycholesterol level was 35.4 ng ml À1. The mean 4b-hydroxycholesterol level (P ¼ 0.0001) and the 4b-hydroxycholesterol/cholesterol ratio (P ¼ 0.004) were higher in women than in men. CYP3A5 genotype significantly correlated with the plasma 4b-hydroxycholesterol concentration (P ¼ 0.003) and 4b-hydroxycholesterol/ cholesterol ratio (P ¼ 0.0002). The omeprazole/omeprazole sulfone ratio was significantly correlated with 4b-hydroxycholesterol and 4b-hydroxycholesterol/cholesterol ratio in CYP3A5*0/*0 genotypes but not in individuals carrying the CYP3A5*1 allele. No correlation of omeprazole/omeprazole sulfone ratio with sex or CYP3A5 genotype was observed. A clear gene-dose effect implies plasma 4b-hydroxycholesterol level as a useful endogenous biomarker for total CYP3A activity (CYP3A5 plus CYP3A4) whereas the omeprazole/omeprazole sulfone ratio reflects mainly CYP3A4 activity. Sex and CYP3A5 genotype influence total CYP3A activity. Ethiopians display high total CYP3A activity and a unique distribution of CYP3A5 variant alleles not described hitherto.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

et al. 2010

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“…Thus, the GSTM1-null should facilitate the formation of AFB1-DNA adducts in the cells. Several reports have shown that GSTM1 polymorphism is associated with the level of serum AFB1-albumin adducts [5,22,23] . For example, McGlynn et al [5] investigated the impact of this polymorphism on detoxification phenotype in 49 adult healthy males.…”

Section: Discussionmentioning

confidence: 99%

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

Long

Deng

2009

Chin. J. Cancer Res.

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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.

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“…Kensler et al, (1998) found no association between AF-alb and GSTM1 genotype in adults from Qidong County, People's Republic of China. More recently, however, CYP3A5 genotypes associated with high expression were shown to have higher AF-alb levels in Gambian adults (Wojnowski et al, 2004).…”

Section: Human Variability and Factors Affecting Biotransformationmentioning

confidence: 98%

Opinion of the scientific panel on contaminants in the food chain [CONTAM] related to the potential increase of consumer health risk by a possible increase of the existing maximum levels for aflatoxins in almonds, hazelnuts and pistachios and derived prod

2007

EFSA Journal

129

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SUMMARYAflatoxins are produced by moulds that are especially found in areas with hot, humid climates. They are most likely to contaminate tree nuts, ground nuts, figs and other dried fruits, spices, crude vegetable oils, cocoa beans and maize. Because aflatoxins are considered to be genotoxic and carcinogenic, it is not possible to identify an intake without risk, and the European Union (EU) introduced regulations for these toxins in 1998, at levels considered to be as low as reasonably achievable. Recent discussions in Codex Alimentarius have proposed setting worldwide a maximum level for total aflatoxins in unprocessed almonds, hazelnuts and pistachios, higher than that currently in force in the EU. As a result, the Scientific Panel on Contaminants in the Food chain (CONTAM) was asked to advise on the potential increase in risks to consumer health associated with a proposed change of the currently existing EU maximum level of 4 µg/kg for total aflatoxins (sum of aflatoxins B1, B2, G1 and G2) in almonds, hazelnuts and pistachios to 8 or 10 µg/kg, taking into account consumption patterns of these nuts in the EU, and intake of aflatoxins from other foods.About 40,000 analytical results on occurrence of aflatoxins in various food commodities were considered by the CONTAM Panel. Aflatoxins were not detected in about 75% of the samples tested, i.e. if present they were below the limit of detection of the methods used, which varied for different sets of data. For those samples where aflatoxins were detectable, aflatoxin B1 was generally the major contributor to total aflatoxins. As a conservative estimate for the purposes of the evaluation, the CONTAM Panel assumed that total aflatoxins would be a maximum of twice the level of aflatoxin B1. The CONTAM Panel also received data relating to concentrations of aflatoxin M1 (the major metabolite of aflatoxin B1) in commercial milk samples. For almost all of these data, the values for the aflatoxin M1 concentration were below 0.05 µg/kg and taking into account the lower carcinogenic potency of M1 the Panel did not consider these data further.In order to assess the impact of a possible change in the maximum levels for almonds, hazelnuts and pistachios, the CONTAM Panel estimated dietary exposure excluding occurrence data above 4, 8 and 10 µg/kg, respectively. These calculations indicated that increasing the maximum levels of total aflatoxins from 4 to 8 or 10 µg/kg could result in slight absolute increases in total aflatoxins in almonds, hazelnuts and pistachios, but that the mean concentrations would remain below 1 µg/kg according to the submitted test results.Assessment of the impact of these potential increases in aflatoxin occurrence requires consideration of both the consumption of these three types of nut and the intake from other dietary sources. Robust data on other sources of dietary exposure, representative of all Member States, were not available to the CONTAM Panel. Evaluation of the few available national dietary exposure data indicated that a reasonable approxi...

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Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in The Gambia, West Africa

Abstract: The CYP3A5 polymorphism is associated with increased levels of the mutagenic AFB1-exo-8,9-epoxide, particularly in individuals with low CYP3A4, and this may modulate individual risk of HCC.

Cited by 60 publications

References 18 publications

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

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

Opinion of the scientific panel on contaminants in the food chain [CONTAM] related to the potential increase of consumer health risk by a possible increase of the existing maximum levels for aflatoxins in almonds, hazelnuts and pistachios and derived prod

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