The metabolism of 2,6-di- tert .-butyl-4-hydroxymethylphenol (Ionox 100) in the dog and rat

Self Cite

1. Up to one-third of a single oral dose of Ionox 201 was absorbed in rats. 2. In rats dosed with [(14)C]Ionox 201 86.8-97.2% of the label is excreted in the faeces in 24 days (much of this is eliminated in the first 4 days after dosage), 5.6% in the urine and not more than 0.8% in the exhaled air; 5.0% of (14)C is present in the carcass and viscera after removal of the gut, and most of this is in the fatty tissues. 3. About 65.0% of (14)C in the faeces is due to unchanged antioxidant, 30.0% to 3,5-di-tert.-butyl-4-hydroxybenzoic acid, 3.5% to unidentified polar constituent(s), 1.4% to 3,5-di-tert.-butyl-4-hydroxybenzaldehyde and 0.1% to 3,3',5,5'-tetra-tert.-butyl-4-,4'-stilbenequinone. A variable proportion of (14)C in the urine is due to 3,5-di-tert.-butyl-4-hydroxybenzoic acid (40-60%) and the remainder (60-40%) to the ester glucuronide, when the animals were treated with different doses of antioxidant. In eight individual animals dosed with 6.78mg. of [(14)C]Ionox 201, one-third of (14)C in the bile is due to the free acid, 45% to the ester glucuronide, 20% to an unidentified constituent and 2% to unchanged antioxidant, and, in two animals dosed with 13.56mg., there is a small proportion of free acid and a larger proportion of ester glucuronide. About 80% of (14)C in the body fat is due to unchanged antioxidant, 19% to the free acid and 1% to 3,5-di-tert.-butyl-4-hydroxybenzaldehyde. 4. At least 36.2% of a single oral dose of Ionox 201 is metabolized: 3,5-di-tert.-butyl-4-hydroxybenzoic acid accounts for 30.2% of a dose, (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid for 1.4%, 3,5-di-tert.-butyl-4-hydroxybenzaldehyde for 1.3%, 3,3',5,5'-tetra-tert.-butyl-4,4'-stilbenequinone for 0.1% and unidentified polar metabolite(s) for 3.2%. 5. The metabolism of Ionox 201 in vivo is closely related to its antioxidant action in vitro.

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

The metabolism of di-(3,5-di-tert.-butyl-4-hydroxybenzyl) ether (Ionox 201) in the rat

Wright¹,

Crowne²,

Hathway³

1967

Self Cite

“…Dacre's (1961) own evidence for this metabolite is not entirely satisfactory, as a sample of the authentic glycine conjugate, when subjected to chromatography under the conditions that he described, gives Rp values different from those that he claimed. Doubt about Dacre's (1961) evidence has also been expressed by Wright, Akintonwa, Crowne & Hathway (1965), who failed to find this conjugate in their study of the metabolism of Ionox 100 by the rat and the dog. BHTacid can be extracted by ether at pH6; this suggests that it is a very weak acid, and possibly too weak to form the acyl-CoA derivative, which is stated by Schachter & Taggart (1954) to mediate the glycine conjugation of benzoic acid derivatives.…”

Section: Identification Of Metabolitesmentioning

confidence: 96%

“…Although aromatic hydrocarbons are known to yield mercapturic acids through some intermediate oxidation product (Boyland & Sims, 1958), this has not been reported for aliphatic hydrocarbons or for alkyl substituents on aromatic rings. lonox 100 (Wright et al 1965) does not form a mercapturic acid, and though a benzyl mercapturic acid is known to be Table 4. Metabolites in rat urine and bile, and in human urine Rat urine results are based on Expt.…”

Section: Identification Of Metabolitesmentioning

confidence: 99%

The metabolism of 3,5-di-tert.-butyl-4-hydroxytoluene in the rat and in man

Daniel¹,

Gage²,

Jones³

1968

1. The major metabolites of 3,5-di-tert.-butyl-4-hydroxytoluene (BHT) in the rat are 3,5-di-tert.-butyl-4-hydroxybenzoic acid (BHT-acid), both free (9% of the dose) and as a glucuronide (15%), and S-(3,5-di-tert.-butyl-4-hydroxybenzyl)-N-acetylcysteine. 2. The mercapturic acid does not appear to derive from the usually accepted enzyme mechanism, and may involve a non-enzymic reaction between BHT free radical and cysteine. 3. The ester glucuronide and mercapturic acid found in rat urine are also the major metabolites in rat bile and must be responsible for the enterohepatic circulation. 4. Free BHT-acid is the main component in rat faeces. 5. In man, BHT-acid, free and conjugated, is a minor component in urine, and the mercapturic acid is virtually absent. The bulk of the radioactivity is excreted as the ether-insoluble glucuronide of a metabolite in which the ring methyl group and one tert.-butyl methyl group are oxidized to carboxyl groups, and a methyl group on the other tert.-butyl group is also oxidized, probably to an aldehyde group. 6. These differences in metabolism by the rat and by man are sufficient to account for the difference in excretion by the two species.

“…second consists of the benzyl alcohol of compound (I), i.e. 2,6-di-t-butyl-4-hydroxymethylphenol (compound IV) (Aoki, 1962;Wright et al, 1965), its aldehyde (Daniel et al, 1967), and the corresponding benzoic acid (Dacre, 1961;Gilbert & Golberg, 1967). Also, the oxidation of a t-butyl substituent of compound (I) in rabbits has been reported (Daniel et al., 1968) but not confirmed (Holder et al, 1970).…”

mentioning

confidence: 99%

Ring hydroxylation of di-t-butylhydroxytoluene by rat liver microsomal preparations

Shaw

Chen

1972

3,5-Di-t-butylhydroxytoluene (compound I) was converted into 4-hydroperoxy-4-methyl-2,6-di-t-butylcyclohexa-2,5-dienone (compound II), 4-hydroxy-4-methyl-2,6-di-t-butylcyclohexa-2,5-dienone (compound III) and 2,6-di-t-butyl-4-hydroxymethylphenol (compound IV) by rat liver microsomal preparations in the presence of NADPH and air. The oxidation of compound (I) by m-chloroperbenzoic acid also produced the same compounds. These results suggest that hydroperoxide can be an intermediate in aromatic hydroxylation and that biological oxygenations resemble per-acid reactions.