Food Additives Metabolism, Fate of Butylated Hydroxyanisole in Man and Dog

Astill, B. D.; Mills, John W.; Fassett, D. W.; Roudabush, Robert L.; Terhaar, C. J.

doi:10.1021/jf60122a015

Cited by 57 publications

(33 citation statements)

References 4 publications

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“…Using this approach, we have investigated the contribution of oxygen radicals to the induction of micronuclei by two quinone-forming compounds, HQ and tBHQ. HQ and tBHQ are metabolites which are formed in vivo following exposure to benzene and BHA, respectively [Astill et al, 1962;Rickert et al, 19791. Once present, HQ and tBHQ may form their respective quinone species 1 ,Cbenzoquinone (BQ) and tertiary-butylquinone (tBQ) either through autoxidation or enzymatic oxidation.…”

Section: Ofmentioning

confidence: 99%

Role of oxygen radicals in the chromosomal loss and breakage induced by the quinone‐forming compounds, hydroquinone and tert‐butylhydroquinone

Dobo

Eastmond

1994

Environ and Mol Mutagen

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The mechanisms by which two quinone-forming compounds, hydroquinone (HQ) and tert-butyl-hydroquinone (tBHQ), induce chromosomal loss and breakage in a prostaglandin H synthase-containing V79 cell line have been investigated using the cytokinesis-block micronucleus assay with CREST antibody staining. Increased frequencies of CREST-positive micronuclei (indicating chromosome loss) and CREST-negative micronuclei (indicating chromosome breakage) were observed following exposure of cells to HQ and tBHQ. The formation of micronuclei by HQ, but not tBHQ, was dependent on arachidonic acid supplementation, indicating activation by prostaglandin H synthase. Since the oxidation of hydroquinones can result in the generation of oxygen radicals, the contribution of oxygen radicals to the formation of chromosomal alterations induced by HQ and tBHQ was investigated. In the presence of a superoxide-generating system consisting of hypoxanthine and xanthine oxidase, a significant increase in micronucleated cells was observed. These induced micronuclei consisted exclusively of CREST-negative micronuclei and their formation was completely inhibited by pretreatment with catalase. Catalase also significantly inhibited the CREST-negative micronuclei induced by HQ and tBHQ. In addition, glutathione treatment inhibited both CREST-positive and negative micronuclei induced by these phenolic compounds. These results indicate that both chromosome loss and breakage are induced by these two quinone-forming agents. Reactive oxygen species contribute to the chromosomal breakage induced by HQ and tBHQ but the observed chromosomal loss appears to result from other mechanisms such as an interference of quinone metabolites with spindle formation.

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Section: Ofmentioning

confidence: 99%

Role of oxygen radicals in the chromosomal loss and breakage induced by the quinone‐forming compounds, hydroquinone and tert‐butylhydroquinone

Dobo

Eastmond

1994

Environ and Mol Mutagen

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“…tBHQ Activates ERK2 in Hep G2 Cells but Not in HeLa Cells and Is Also a Weak Inducer of JNK1-tBHQ is a major metabolite of BHA, as demonstrated in many animal species as well as in human (18,19). A number of previous studies implicated that this compound may mediate many biological activities of BHA, including anti-carcinogenic and carcinogenic effects.…”

Section: Bha Stronglymentioning

confidence: 99%

“…One of the major metabolites of BHA, as shown in dogs (18), rats, and man (19), and in rat liver microsomes (20), is the demethylated product, tert-butylhydroquinone (tBHQ), which also exhibits anti-carcinogenic properties in some animal models of cancer in a manner similar to that described for BHA. This includes modulation of the enzyme systems responsible for metabolic activation or deactivation of chemical carcinogens (21).…”

mentioning

confidence: 98%

Butylated Hydroxyanisole and Its Metabolitetert-Butylhydroquinone Differentially Regulate Mitogen-activated Protein Kinases

Tan

Kong

1997

Journal of Biological Chemistry

105

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Phenolic antioxidant butylated hydroxyanisole (BHA) is a commonly used food preservative with broad biological activities, including protection against acute toxicity of chemicals, modulation of macromolecule synthesis and immune response, induction of phase II detoxifying enzymes, and especially its potential tumorpromoting activities. Understanding the molecular basis underlying these diverse biological actions of BHA is thus of great importance. Here we demonstrate that BHA is capable of activating distinct mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinase 2 (ERK2), and c-Jun N-terminal kinase 1 (JNK1). Activation of ERK2 by BHA was rapid and transient, whereas the JNK1 activation was relatively delayed and persistent. A major metabolite of BHA, tertbutylhydroquinone (tBHQ), also activated ERK2 but weakly stimulated JNK1 activity. Furthermore, tBHQ activation of ERK2 was late and prolonged, showing a kinetics different from that induced by BHA. ERK2 activation by both compounds required the involvement of an upstream signaling kinase MAPK/ERK kinase (MEK), as evidenced by the inhibitory effect of a MEK inhibitor, PD98059. Pretreatment with N-acetyl-L-cysteine, glutathione, or vitamin E attenuated ERK2 but not JNK1 activation by BHA and tBHQ. Modulation of intracellular H 2 O 2 levels by direct addition of catalase or pretreatment with a catalase inhibitor, aminotriazole, also affected BHA-and tBHQ-stimulated ERK2 activity but not JNK1, indicating the involvement of oxidative stress in the ERK2 activation by these two compounds. However, we did not observe any generation of H 2 O 2 after exposure of cells to BHA or tBHQ using a H 2 O 2 -sensitive fluorescent probe, 2,7-dichlorofluorescein diacetate. Instead, BHA and tBHQ substantially reduced the amount of intracellular H 2 O 2 . Furthermore, BHA and tBHQ activation of ERK2 was strongly inhibited by ascorbic acid and a peroxidase inhibitor, sodium azide, suggesting the potential role of phenoxyl radicals and/or their derivatives. Taken together, our results indicate that (i) BHA and its metabolite tBHQ differentially regulate MAPK pathways, and (ii) oxidative stress due to the generation of reactive intermediates, possibly phenoxyl radicals but not H 2 O 2 , is responsible for the ERK2 activation by BHA and tBHQ, whereas the JNK1 activation may require a distinct yet unknown mechanism.

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“…In rats and rabbits most of an oral dose is excreted in the urine within 24 h as the 4-0-glucuronide (50-80%) with smaller amounts present as the 4_0_sulphate.152-154 In the dog, around 60% is excreted unchanged in the faeces and the remainder in the urine as the 4-0-sulphate with some tertiary butylhydroquinone (TBHQ) , an unidentified phenol and a small proportion as the 4-0-glucuronide. 155 There is little evidence for tissue retention of BRA in rats, dogs, pigs or pullets. 154,156-159 " In humans, gastrointestinal absorption is also rapid,16O but much lower doses in humans are required to produce a given plasma BHA level than in rats, an oral dose of around 0·5 mg/kg bw in humans being comparable to 200 mg/kg bw in rats.159 This could have implications for risk assessment if the effects of BHA on the rat forestomach (see later) are mediated systemically and are thought to have implications for human health.…”

Section: Butylated Hydroxyanisolementioning

confidence: 99%