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

Shaw, Yon-Shong; Chen, Chiadao

doi:10.1042/bj1281285

Cited by 34 publications

(4 citation statements)

References 34 publications

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“…BHT is metabolized in the body through oxidations of the benzyl and tert -butyl parts to yield two distinct alcohols 22 , 23 , 24 ) . In addition, 4-hydroperoxy derivative of BHT and quinone methide are identified in vitro and these are proposed to link to the pulmonary toxicity in mice 25 , 26 ) . The formation of the peroxy-derivative is inhibited by carbon monoxide and SKF525-A, suggesting the P450-mediated production, although no data is available for human CYP enzyme(s) involved in the formation of the peroxy-derivative.…”

Section: Resultsmentioning

confidence: 99%

Deciphering Key Interactions of Ligands with CYP3A4-Template* system

et al. 2021

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Cytochrome P450 (CYP)-mediated metabolisms are often associated with biological and toxicological events of chemicals. A major hepatic enzyme, CYP3A4, showed clear distinctions on their catalyses even among ligands having resemble structures. To better understand mechanisms of their distinct catalyses, possible associations of ligand interactions at specific parts of CYP3A4 residues were investigated using CYP3A4-Template system developed (DMPK 2019 and 2020). A placement was available selectively for CYP3A4-mediated R-thalidomide 5-oxidation on Template, but not for the 5'-oxidation and the S-isomer oxidations. Similar placements were generated for pomalidomide (4-amino-thalidomide), but not for a poor ligand, lenalidomide (3-deoxy-pomalidomide). The latter ligand took placements lacking IJK-Interaction or sticking the 4-amino part beyond the facial-side wall on Template. A placement was available for the tert-butyl oxidation of terfenadine, but not for an analog, ebastine. Their interactions with upper-Cavity-2 residue were expected to differ at their sites of oxygen substituents. Some phenolic antioxidants behave distinctly toward biological oxidations in vitro and in vivo. Butylated hydroxytoluene is oxidized to the peroxy-derivative in vitro, but solely to the oxidized metabolites at the benzyl and tert-butyl methyl positions in vivo. Involvement of CYP3A4 were suggested for all the three reactions from the placements on Template. Tocopherols were also applied on Template for the oxidations for chroman and side-chain terminals. The primary placement was suggested to undergo the futile-recycling through formation of the peroxide intermediate subsequently to lead the substantial lack of the CYP3A4-mediated oxidation. These data suggest the effectiveness of CYP3A4-Template assessment to understand the causal basis of poor oxidations and also to verify the in vivo contribution of CYP3A4-mediated peroxidative reactions.

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Section: Resultsmentioning

confidence: 99%

Deciphering Key Interactions of Ligands with CYP3A4-Template* system

et al. 2021

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“…BHT undergoes biotransformational processes not only in foods, natural environments, such as air, dust, soils, or water (Fries and Püttmann , ; Fernandez‐Alvarez and others ; Rodil and others , ), but also in living organisms. The metabolism of BHT is very complex and it has been investigated in different animal species, such as rats (Daniel and Gage ; Ladomery and others ; Daniel and others ; Holder and others ; Shaw and Chen ; Matsuo and others ; Conning and Phillips ), mice (Matsuo and others ), rabbits (Dacre ; Conning and Phillips ), chickens (Frawley and others ), monkeys (Allen ; Conning and Phillips ), dogs (Gage ), and also in humans (Daniel and others , ; Holder and others ; Conning and Phillips ). As BHT undergoes several reactions during biotransformation, a large number of intermediate metabolites have been identified.…”

Section: Biotransformation Of Bhtmentioning

confidence: 99%

2,6‐Di‐Tert‐Butyl‐Hydroxytoluene and Its Metabolites in Foods

Nieva‐Echevarría

Manzanos

Goicoechea

et al. 2014

Comp Rev Food Sci Food Safe

143

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2,6-Di-tert-butyl-hydroxytoluene (BHT, E-321) is a synthetic phenolic antioxidant which has been widely used as an additive in the food, cosmetic, and plastic industries for the last 70 y. Although it is considered safe for human health at authorized levels, its ubiquitous presence and the controversial toxicological data reported are of great concern for consumers. In recent years, special attention has been paid to these 14 metabolites or degradation products: BHT-CH 2 OH, BHT-CHO, BHT-COOH, BHT-Q, BHT-QM, DBP, BHT-OH, BHT-OOH, TBP, BHQ, BHT-OH(t), BHT-OH(t)QM, 2-BHT, and 2-BHT-QM. These derived compounds could pose a human health risk from a food safety point of view, but they have been little studied. In this context, this review deals with the occurrence, origin, and fate of BHT in foodstuffs, its biotransformation into metabolites, their toxicological implications, their antioxidant and prooxidant properties, the analytical determination of metabolites in foods, and human dietary exposure. Moreover, noncontrolled additional sources of exposure to BHT and its metabolites are highlighted. These include their carryover from feed to fish, poultry and eggs, their presence in smoke flavorings, their migration from plastic pipelines and packaging to water and food, and their presence in natural environments, from which they can reach the food chain.

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“…Chemical studies have identified epoxides (Grover et ~' 1971), hydroperoxides (Shaw and Chen, 1972), and other reactive compounds as possible intermediates, but so far neither these nor spectroscopic methods have succeeded in delineating the main reaction pathway. We have recently begun an extensive study of the magnetic circular dichroism (Mco 1 ) of a variety of hemoproteins and their derivatives and of some model heme compounds (Vickery; Nozawa and Sauer, in ·preparation).…”

Section: ~S-mentioning

confidence: 99%