Butylated hydroxytoluene modulates DNA methylation in rats

Vanyushin, B. F.; Lopatina, N G; Wise, Carolyn; Fullerton, Floyd R.; Poirier, Lionel A.

doi:10.1046/j.1432-1327.1998.2560518.x

Cited by 15 publications

(7 citation statements)

References 49 publications

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“…The distribution of hmC and mC in different mouse tissues is depicted in Figure 4A and 4B . We measured uniform amounts of mC that represent 4.30±0.22% of dG in all tissues in agreement with previous reports [11], [30], [31]. The only exception is nasal epithelia with a slightly lower value.…”

Section: Resultssupporting

confidence: 91%

Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates

et al. 2010

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5–Hydroxymethylcytosine (hmC) was recently detected as the sixth base in mammalian tissue at so far controversial levels. The function of the modified base is currently unknown, but it is certain that the base is generated from 5-methylcytosine (mC). This fuels the hypothesis that it represents an intermediate of an active demethylation process, which could involve further oxidation of the hydroxymethyl group to a formyl or carboxyl group followed by either deformylation or decarboxylation. Here, we use an ultra-sensitive and accurate isotope based LC-MS method to precisely determine the levels of hmC in various mouse tissues and we searched for 5–formylcytosine (fC), 5-carboxylcytosine (caC), and 5–hydroxymethyluracil (hmU) as putative active demethylation intermediates. Our data suggest that an active oxidative mC demethylation pathway is unlikely to occur. Additionally, we show using HPLC-MS analysis and immunohistochemistry that hmC is present in all tissues and cell types with highest concentrations in neuronal cells of the CNS.

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Section: Resultssupporting

confidence: 91%

Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates

et al. 2010

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“…The 5-Me dC values are significantly lower in the hypothalamus and here we indeed detect high 5-HOMe dC values. In contrast, and in accord with the literature, [14] we found that the 5-Me dC values are stable at a typical value of around 4.5 % in all other tissues, while the 5-HOMe dC values vary significantly. This suggests that 5-HOMe dC has a function that is not correlated with the 5-Me dC value.…”

supporting

confidence: 92%

Quantification of the Sixth DNA Base Hydroxymethylcytosine in the Brain

et al. 2010

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Mind over matter: LC‐MS has allowed the amount of the post‐replicatively formed DNA base 5‐hydroxymethylcytosine (see picture; left) to be quantified in brain tissue. The nucleoside is most abundant in areas that are associated with higher cognitive functions, and its content in mouse hippocampi seems to increase with age. The new method enables hydroxymethylcytosine to be quantified with unprecedented accuracy.

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“…These studies indicate that BHT may exert effects at doses far above the ADI, and some of these effects may be attributed to BHT working as a pro-oxidant at high concentrations, indirectly by inhibiting antioxidant defences through the depletion of nonprotein thiols and by covalent modifications of protective enzymes (Sun et al, 2003). Various mechanisms have been suggested for the occurrence of lung and hepatic tumours in certain strains of mice and rats, and it seems that these effects may be due to many factors, such as inhibition of gap junctional intercellular communication (Guan et al, 1995;Trosko et al, 1990), increase in mitochondrial permeability, epigenetic changes due to induction of DNA methyl transferases (Vanyushin et al, 1998), induction of oxidative stress by the quinone methide metabolites (Faine et al, 2006), inhibition of antioxidant enzymes such as carbonyl reductase (Shearn et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Scientific Opinion on the re‐evaluation of butylated hydroxytoluene BHT (E 321) as a food additive

2012

EFS2

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The Panel on Food Additives and Nutrient Sources added to Food (ANS) delivers an opinion reevaluating the safety of butylated hydroxytoluene (BHT) (E 321). BHT is an authorised synthetic antioxidant that was previously evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the latest in 1996 and the EU Scientific Committee for Food (SCF) in 1987. The SCF established an ADI of 0-0.05 mg/kg bw/day based on thyroid, reproduction and haematological effects in the rat. JECFA allocated an ADI of 0-0.3 mg/kg bw/day for BHT based on effects in the reproduction segments and hepatic enzyme induction seen in two separate 2-generation studies in rats. The Panel concluded that BHT is not of concern with respect to genotoxicity and that any carcinogenicity would be thresholded. After the last SCF evaluation, two new 2-generation studies have been reported which were the basis for the ADI set by JECFA. Both studies revealed a NOAEL of 25 mg/kg bw/day. Overall, the Panel concluded that the present database gives reason to revise the ADI of 0.05 mg/kg bw/day. Based on the NOAEL of 25 mg/kg bw/day and an uncertainty factor of 100, the Panel derived an ADI of 0.25 mg/kg bw/day. Since the NOAEL of 25 mg/kg bw/day is below the BMDL10 value of 247 mg/kg bw/day derived from the data for the incidence of hepatocellular carcinomas in male rats, the Panel concluded that this NOAEL also covers the hepatocellular carcinomas observed in the long-term studies with BHT. Exposure of adults to BHT is unlikely to exceed the newly derived ADI at the mean and at the 95th percentile. For exposure of children to BHT from its use as food additive, the Panel noted that it is also unlikely that this ADI is exceeded at the mean, but is exceeded for some European countries (Finland, The Netherlands) at the 95th percentile. SUMMARYFollowing a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion on the re-evaluation of butylated hydroxytoluene (BHT) (E 321) as a food additive.BHT (E 321) is a synthetic antioxidant authorised as a food additive in the EU that was previously evaluated by the EU Scientific Committee for Food (SCF) in 1987 and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) several times, the latest in 1996.The SCF established an ADI of 0-0.05 mg/kg bw/day based on thyroid, reproduction and haematological effects in the rat. At its last evaluation JECFA allocated an ADI of 0-0.3 mg/kg bw/day for BHT, based on effects in the reproduction segments and hepatic enzyme induction, seen in two separate 2-generation studies in rats. These studies were probably not available at the time of the SCF evaluation.Specifications have been defined in the EU legislation Directive 2008/48/EC and by JECFA (JECFA, 2006). The purity is specified to be not less than 99%.Absorption, distribution, metabolism and excretion of BHT have been studied in mice, rats, rabbits, chickens, monkeys and humans. Overall, these studies show that BHT is r...

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Butylated hydroxytoluene modulates DNA methylation in rats

Cited by 15 publications

References 49 publications

Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates

Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates

Quantification of the Sixth DNA Base Hydroxymethylcytosine in the Brain

Scientific Opinion on the re‐evaluation of butylated hydroxytoluene BHT (E 321) as a food additive

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