Cyclic metabolic pathway of a butylated hydroxytoluene by rat liver microsomal fractions

Chen, Chiadao; Shaw, Yon-Shong

doi:10.1042/bj1440497

Cited by 40 publications

(11 citation statements)

References 11 publications

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“…What we have found in mitochondria at low concentrations of BHT was actually the opposite of what is normally expected from this compound, namely an antioxidant action . That this action occurs at very low concentrations in intact mitochondria, starting at 10 −8 M, can be an important detail because, as discussed above, it is highly probable that the concentrations of free (unbound) BHT in the cell are very low.…”

Section: Discussionmentioning

confidence: 99%

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A reappraisal of the proposed metabolic and antioxidant actions of butylated hydroxytoluene (BHT) in the liver

Castro

Bracht

Comar

et al. 2017

J Biochem & Molecular Tox

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Butylated hydroxytoluene (BHT) was investigated for its metabolic actions in the perfused rat liver. Contrary to what is expected from an uncoupler, BHT up to 500 μM did not stimulate oxygen uptake nor did it inhibit gluconeogenesis from lactate. Transformation of fructose into glucose was also not affected by BHT; only lactate production was slightly increased at the concentration of 100 μM. The uncoupling effect of BHT in isolated mitochondria was confirmed, but only at concentrations above 10 μM; uncoupling at lower concentrations, 10 to 10 M, could not be confirmed. BHT, however, increased reactive oxygen species (ROS) production in isolated mitochondria, starting at the concentration of 10 M. This is the opposite of what can be expected from a compound with proven ex vivo antioxidant action. One cannot exclude the possibility that, in mitochondria, stimulation of ROS production rather than uncoupling could be the most significant effect of BHT.

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Section: Discussionmentioning

confidence: 99%

“…Butylated hydroxytoluene (BHT) is amply utilized as antioxidant in industrially processed foods, cosmetics, pharmaceutical, and petrochemical products . Its chemical structure is shown as an inset in Figure .…”

Section: Introductionmentioning

confidence: 99%

A reappraisal of the proposed metabolic and antioxidant actions of butylated hydroxytoluene (BHT) in the liver

Castro

Bracht

Comar

et al. 2017

J Biochem & Molecular Tox

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“…The study was comparable to OECD TG 417 with acceptable restrictions. Briefly, female F344 rats (3-4/ group) received 0.03 mg/kg bw 14 C-labelled phenol via oral administration. Radioactivity in urine and faeces was analysed after sampling in metabolism cages; the animals were sacrificed 72 h after application and radioactivity in organs, carcass and washings determined.…”

Section: Toxicokinetic Differencesmentioning

confidence: 99%

“…The main metabolic pathway leads to the alcohol, aldehyde and acid derivatives by stepwise oxidation of the 4 -methyl group [13]. However, a cyclic metabolic pathway via quinoid metabolites (i.e., 2,6-ditertbutyl-4-hydroperoxy-4-methyl-2,5-cyclohexadienone and 2,6ditertbuty-4-hydroxy-4-methyl-2,5-cyclohexadienone) has been described in rat liver microsomes [14]. Yamamoto et al detected reactive metabolites (i.e., 2,6-ditertbutyl-pbenzoquinone and 2,6-ditertbutylhydroquinone) possibly also a result from this pathway [15].…”

Section: Toxicokinetic Differencesmentioning

confidence: 99%

Read-across for rat oral gavage repeated-dose toxicity for short-chain mono-alkylphenols: A case study

Mellor

Schultz

Przybylak

et al. 2017

Computational Toxicology

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Short-chain mono-alkylphenols provide an example of where a category-approach to read-across may be used to estimate the repeated-dose endpoint for a number of derivatives. Specifically, the NOAELs of 50 mg/kg bw/d for mono-methylphenols based on a LOAEL of very low systemic toxicity can be read across with confidence to untested mono-alkylphenols in the category. These simple alkylphenols are non-reactive and exhibit an unspecific, reversible polar narcosis mode of toxic action. Briefly, polar narcotics act via unspecific, reversible interactions with biological membranes in a manner similar to cataleptic anaesthetics. The readacross premise includes rapid and complete absorption via the gastrointestinal tract, distribution in the circulatory system, first-pass Phase 2 metabolism in the liver, and elimination of sulphates 3 and glucuronides in the urine. Thus, toxicokinetic parameters are considered to be similar and have the same toxicological significance. Five analogues have high quality experimental oral repeated-dose toxicity data (i.e., OECD TG 408 or OECD TG 422). These repeated-dose toxicity test results exhibit qualitative consistency in symptoms. Typical findings include decreased body weight and slightly increased liver and kidney weights which are generally without concurrent histopathological effects. The sub-chronic findings are quantitatively consistent with the No Observed Adverse Effect Level (NOAEL) of ≥ 50 mg/kg bw/d. Chemical similarity between the analogues is readily defined, and data uncertainty associated with the similarities in toxicokinetic properties, as well as toxicodynamic properties, are low. Uncertainty associated with mechanistic relevance and completeness of the read-across is lowto-moderate, largely because there is no adverse outcome pathway or intermediate event data. Uncertainty associated with mechanistic relevance and completeness of the read-across is reduced by the concordance of in vivo, in vitro, USEPA toxicity forecaster (ToxCast) results, as well as the in silico data. The rat oral repeated-dose NOAEL values for the source substances can be read across to fill the data gaps of the untested analogues in this category with uncertainty deemed equivalent to results from a TG 408 assessment. .

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“…Recent studies conducted in our laboratory involving P-450 interactions with la (9,11), a 4-methyl-l,4-peroxyquinol (2,6-di-tert-butyl-4-hydro-* Abbreviations: CHP (cumyl hydroperoxide), 2-hydroperoxy-2-phenylpropane; BHT (butylated hydroxytoluene), 2,6-di-tert-butyl-4-methylphenob P-450b, the major phenobarbital-inducible form of cytochrome P-450 from rat liver. 0893-228~/88/2101-0385$01.50/0 peroxy-4-methylcyclohexa-2,5-dienone) produced in biological systems from the antioxidant BHT (12,13), led to the reaction scheme shown in Figure 1. Heterolytic and homolytic 0-0 bond cleavages are represented by pathways I and 11, respectively.…”

Section: Introductionmentioning

confidence: 98%

Fate of free radicals generated during one-electron reductions of 4-alkyl-1,4-peroxyquinols by cytochrome P 450

Yumibe¹,

Thompson²

1988

Chem. Res. Toxicol.

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Free radicals resulting from the one-electron reduction and subsequent homolytic cleavage of oxygen-oxygen bonds by heme proteins are likely to be responsible for some aspects of the toxicity of organic hydroperoxides. In the present work, effects of the 4-alkyl substituent of 2,6-di-tert-butyl-4-alkyl-4-hydroperoxycytohexa-2,5-dienones (1,4-peroxyquinols) on radical production were investigated with microsomal cytochrome P-450 from rat liver. Quinoxy radicals from homolysis of the peroxyquinols underwent beta-scission to produce a quinone and an alkyl radical, and this process occurred with increasing frequency as the stability of the alkyl radical increased. The fate of benzyl and 2-phenylethyl radicals generated from the appropriately substituted peroxyquinols was investigated also. The former was converted to benzyl alcohol, benzaldehyde, and toluene and the latter to 2-phenylethanol, phenylacetaldehyde, ethylbenzene, styrene, and benzaldehyde. Oxygen-18 labeling studies demonstrated that 80-85% of the benzyl alcohol incorporated oxygen from the hydroperoxide and the balance from molecular oxygen. This indicates that the predominant reaction pathway involved recombination between the benzyl radical and the iron-bound hydroxyl radical of the P-450 intermediate complex. By contrast, about 50% of 2-phenylethanol from the 2-phenylethyl radical incorporated oxygen from water and the balance from O2. Two alternative mechanisms are proposed to explain the formation of 2-phenylethanol that contained oxygen from water and the concurrent formation of styrene: (a) oxygen exchange of the P-450 intermediate with water, followed by hydrogen abstraction and radical recombination reactions with the P-450 complex, or (b) oxidation of the radical to the 2-phenylethyl cation followed by proton elimination and hydration.

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Cyclic metabolic pathway of a butylated hydroxytoluene by rat liver microsomal fractions

Cited by 40 publications

References 11 publications

A reappraisal of the proposed metabolic and antioxidant actions of butylated hydroxytoluene (BHT) in the liver

A reappraisal of the proposed metabolic and antioxidant actions of butylated hydroxytoluene (BHT) in the liver

Read-across for rat oral gavage repeated-dose toxicity for short-chain mono-alkylphenols: A case study

Fate of free radicals generated during one-electron reductions of 4-alkyl-1,4-peroxyquinols by cytochrome P 450

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