<i>In vitro</i>transformation of dithiopyr by rat liver enzymes: Conversion of methylthioesters to acids by oxygenases

Feng, Pengfei; Solsten, R. Thomas

doi:10.3109/00498259109043201

Cited by 13 publications

(7 citation statements)

References 7 publications

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“…16). Its transformation by rat liver microsomes leads to the corresponding carboxylic acids such as 35 as main metabolites [43]. This transformation of its thioester functions into carboxylic acids has been found to be catalyzed by monooxygenases, and not esterases.…”

Section: Other Examples Of Oxidative Metabolism Of Thioesters With Inmentioning

confidence: 97%

Sulfenic acids as reactive intermediates in xenobiotic metabolism

Mansuy

Dansette

2011

Archives of Biochemistry and Biophysics

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Sulfenic acid reactive intermediates are formed during the oxidation of cysteine residues of proteins and play key roles in enzyme catalysis, redox homeostasis and regulation of cell signalling. However few data are presently available on the formation and fate of sulfenic acids as reactive intermediates during the metabolism of xenobiotics. This article is a review of the xenobiotic metabolism situations in which the intermediate formation of a sulfenic acid has been reported. Formation of these intermediates has been either proposed on the basis of the isolation of products possibly deriving from sulfenic acids or shown after trapping of the sulfenic acid by specific nucleophiles. This review indicates the different mechanisms by which a sulphur-containing xenobiotic can be metabolized with the intermediate formation of a sulfenic acid. It also indicates the different possible fates of these sulfenic acids that have been reported in the literature. Finally, it discusses the possible implications of the formation of xenobiotic-derived sulfenic acid reactive metabolites in pharmacology and toxicology.

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Section: Other Examples Of Oxidative Metabolism Of Thioesters With Inmentioning

confidence: 97%

Sulfenic acids as reactive intermediates in xenobiotic metabolism

Mansuy

Dansette

2011

Archives of Biochemistry and Biophysics

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“…In an effort to develop a mechanism-based agent that would bind covalently to the protein when oxidized at the w-2-position, we synthesized the monoethyl thioesters of dodecanedioic and hexadecanedioic acids. Although thioesters have not been investigated previously as mechanism-based inactivating agents for cytochrome P450 enzymes, it has been shown that thioester oxidation produces species that react with water to give the corresponding acids or with gutathione to give glutathione conjugates (Chen et al, 1979;Feng & Solsten, 1991).…”

Section: Resultsmentioning

confidence: 99%

Cytochrome P450BM-3 (CYP102): Regiospecificity of oxidation of .omega.-unsaturated fatty acids and mechanism-based inactivation

Shirane

Sui²,

Peterson³

et al. 1993

Biochemistry

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Cytochrome P450BM-3 preferentially oxidized fatty acids with terminal double or triple bonds to the omega-2 hydroxylated fatty acids rather than, respectively, to the epoxide or diacid metabolites. The enzyme is inactivated during catalytic turnover of long, terminally unsaturated fatty acids but not by the analogous medium-length fatty acids. Enzyme inactivation by 17-octadecynoic acid and 16-hydroxy-17-octadecynoic acid is due to alkylation of the prosthetic heme group to given an adduct tentatively identified as N-(2-oxo-3-hydroxy-17-carboxyheptadecyl)protoporphyrin IX by its chromatographic and spectroscopic properties. Catalytic turnover of 17-octadecenoic acid also results in heme modification. Fatty diacid monoethyl thioesters are introduced as a new class of irreversible inhibitors that exploit the omega-2 oxidation specificity of cytochrome P450BM-3. Catalytic oxidation of the monoethyl thioesters of dodecanedioic and hexadecanedioic acids results in enzyme inactivation and formation of the parent diacids as metabolites. Limited tryptic digestion of the enzyme after incubation with the monoethyl thioester of [14C]hexadecanedioic acid shows that the inactivating agent binds covalently to both the heme and flavin domains. This finding, and the observation that glutathione prevents inactivation of the enzyme by the monoethyl thioesters, indicate that a diffusible metabolite, probably the sulfoxide, is responsible for enzyme inactivation. The strong preference for omega-2 allylic or propargylic hydroxylation over terminal pi-bond oxidation is opposite to the usual cytochrome P450 pattern and requires that the enzyme actively suppress terminal pi-bond oxidation. The inference that the enzyme binds and sequesters the terminal carbon in a lipophilic pocket is consistent with the crystal structure of the hemoprotein domain of cytochrome P450BM-3.

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“…Examples of concurrent metabolism via both sulphur and oxygenated functional groups have been reported for various substrates (Black et al, 1993;Feng and Solsten, 1991;Gachon et al, 1988;Karim El Fatih et al, 1988). In all of them, the predominance of S-oxidation pathway has been reported.…”

Section: Iii2 Sulphides Sulphoxides/sulphones and Sulphonatesmentioning

confidence: 98%

Scientific Opinion on Flavouring Group Evaluation 08, Revision 5 (FGE.08Rev5): Aliphatic and alicyclic mono‐, di‐, tri‐, and polysulphides with or without additional oxygenated functional groups from chemical groups 20 and 30

Flavourings¹

2012

EFS2

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The CEF Panel of the European Food Safety Authority was requested to evaluate 80 flavouring substances in the Flavouring Group Evaluation 08, Revision 4, using the Procedure in Commission Regulation (EC) No 1565/2000. Since the publication of the last revision of this FGE, the EFSA has been requested to evaluate additional toxicological data submitted for two flavouring substances, one substance 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane .006], which support the evaluation of the candidate substance 2,5-dihydroxy-1,4-dithiane .134] and one on the candidate substance spiro(2,4-dithia-1-methyl-8-oxabicyclo[3.3.0]octane-3,3'-(1'-oxa-2'-methyl)-cyclopentane) and spiro(2,4-dithia-6-methyl-7-oxabicyclo[3.3.0]octane-3,3'-(1'-oxa-2'-methyl)-cyclopentane) .007], which have been included in the present revision of FGE.08. For the substances methyl methanethiosulphonate ], 2-methylbutane-2-thiol ], 2-methylpropane-2-thiol .174], ethyl-2-mercapto-2-methyl propanoate .304] and 2,4,4-trimethyl-1,3-oxathiane there is an indication of a genotoxic potential in vitro. Therefore, without further genotoxicity data, the Panel concluded that the Procedure could not be applied to these five substances. For four substances, 3-mercaptooctanal 4 Editorial changes have been made on pages 1 and 2. The changes do not affect the overall conclusions of the opinion. To avoid confusion, the original version of the Opinion has been removed from the website, but it is available on request.Flavouring Group Evaluation 08, Revision 5EFSA Journal 2012;10(7):2837 2 one ] no data on use as flavouring substances in Europe are available and no intake figures could be calculated, which preclude the evaluation of the four substances using the Procedure. The remaining 71 substances were evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that 59 substances do not rise safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. For 12 substances 12.094, 12.097, 12.100, 12.112, 12.116, 12.120, 12.164, 12.167, 12.199, 15.102 and 15.125 no: 15.007] has been reconsidered after submission of an explanatory note from EFFA.Additional information on specifications and/or stereoisomeric/positional composition submitted for 12.163, 12.164, 12.250, 12.266, 12.277, 12.278, 12.298, 12.300, 12.301, 12.302, 12.305, 12.306, 15.007, 15.056, 15.110, 15.134, 16.062, 16.114 and 16.122] has also been included.The present FGE.08Rev5 deals with 80 flavouring substances in total. These are divided into 11 subgroups:Subgroup I) Acyclic sulphides: 12.099, 12.117, 12.124, 12.127, 12.129, 12.152, 12.158, 12.163, 12.166, 12.177, 12.178, 12.181, 12.182, 12.183, 12.214, 12.277, 12.298, 12.299 and 12.306] Subgroup II) Cyclic sulphides: 15.102 and 15.125] Subgroup III) Monothiols: 12.135, 12.136, 12.172, 12.174, 12.180, 12.191, 12.205, 12.250, 12.2...

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In vitrotransformation of dithiopyr by rat liver enzymes: Conversion of methylthioesters to acids by oxygenases

Cited by 13 publications

References 7 publications

Sulfenic acids as reactive intermediates in xenobiotic metabolism

Sulfenic acids as reactive intermediates in xenobiotic metabolism

Cytochrome P450BM-3 (CYP102): Regiospecificity of oxidation of .omega.-unsaturated fatty acids and mechanism-based inactivation

Scientific Opinion on Flavouring Group Evaluation 08, Revision 5 (FGE.08Rev5): Aliphatic and alicyclic mono‐, di‐, tri‐, and polysulphides with or without additional oxygenated functional groups from chemical groups 20 and 30

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