Evidence for thiophene-s-oxide as a primary reactive metabolite of thiophene in vivo: Formation of a dihydrothiophene sulfoxide mercapturic acid

Dansette, Patrick M.; Thang, D. C.; Mansuy, H.

doi:10.1016/s0006-291x(05)81594-3

Cited by 73 publications

(80 citation statements)

References 9 publications

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“…The metabolic activation mechanism is known to be determined by the structure and substitution pattern on the thiophene ring. For example, the thiophene moiety from TA and suprofen undergoes S-oxidation (Dansette et al, 1992(Dansette et al, , 2005O'Donnell et al, 2003;Medower et al, 2008) or thiophene ring epoxidation (O'Donnell, 2003;Dansette et al, 2005), followed by nucleophilic attack on the thiophene ring and deoxygenation or dehydration to form protein adducts or GSH conjugates (Fig. 9).…”

Section: Discussionmentioning

confidence: 99%

“…At the same time, both drugs inactivate CYP2C enzymes (López-Garcia et al, 1994;Jean et al, 1996;O'Donnell et al, 2003;Masubuchi and Horie, 2007;Hutzler et al, 2009). The metabolic activation of thiophene derivatives has been suggested to occur via sulfur oxidation or an epoxidation mechanism (Dansette et al, 1992(Dansette et al, , 2005Valadon et al, 1996;O'Donnell et al, 2003;Medower et al, 2008). The resulting toxicities of thiophenes are thought to be related to the formation of these reactive metabolites.…”

Section: Introductionmentioning

confidence: 99%

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Novel Metabolic Bioactivation Mechanism for a Series of Anti-Inflammatory Agents (2,5-Diaminothiophene Derivatives) Mediated by Cytochrome P450 Enzymes

Yang²,

Shilliday³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The thiophene moiety is considered a structural alert in molecular design in drug discovery, largely because several thiophene-containing drugs, including tienilic acid and suprofen, have been withdrawn from the market because of toxicities. Reactive thiophene intermediates, activated via sulfur oxidation or ring epoxidation, are possible culprits for these adverse side effects. In this work, the metabolic activation of an anti-inflammatory agent, 1-(3-carbamoyl-5-(2,3,5-trichlorobenzamido)thiophen-2-yl)urea), containing a 2,5-diaminothiophene structure, was studied in liver microsomes in the presence of glutathione or N-acetylcysteine as trapping agents. In addition, the glutathione conjugate was detected in bile from a bile duct-cannulated rat study. The structure of the glutathione conjugate was identified by mass spectrometry and 1 H NMR. The glutathione molecule was attached to the thiophene ring, replacing the existing proton. Metabolic phenotyping experiments, using chemical inhibitors or recombinant cytochromes P450 (P450), demonstrated that CYP3A4 was the major P450 enzyme responsible for the metabolic activation, followed by CYP1A2, 2Cs, and 2D6. A novel metabolic activation mechanism is proposed whereby the 2,5-diaminothiophene moiety undergoes oxidation to a 2,5-diimine thiophene reactive intermediate. This mechanism was used to support efforts to eliminate reactive metabolite generation via structural modification of ring substituents using structure-activity relationships. The disruption of formation of the 2,5-diimine reactive intermediate resulted in the elimination of glutathione conjugate formation both in vitro and in vivo and provided a rational approach to mitigating potential safety risks associated with this class of thiophenes in drug research and development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Metabolic Bioactivation Mechanism for a Series of Anti-Inflammatory Agents (2,5-Diaminothiophene Derivatives) Mediated by Cytochrome P450 Enzymes

Yang²,

Shilliday³

et al. 2010

Drug Metab Dispos

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“…In subsequent reactions, the glutathione moiety of this metabolite is converted into an N-acetyl cysteine group. The final metabolite is subsequently excreted via urine, and may be converted spontaneously into 2-thienylmercapturic acid (Dansette et al, 1992). The authors considered the formation of the epoxide intermediate, as suggested by Bray et al (1971), highly unlikely.…”

Section: ])mentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 21, Revision 3 (FGE.21Rev3): Thiazoles, thiophenes, thiazoline and thienyl derivatives from chemical groups 29 and 30

Flavourings¹

2012

EFSA Journal

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The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 59 flavouring substances in the Flavouring Group Evaluation 21, including an additional three substances in this Revision 3, 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 three additional substances 15.079 and 15.135], which have been included in the present revision of FGE.21. Seven of the substances 15.086, 15.090, 15.099, 15.114, 15.119 and 15.133] were considered to have genotoxic potential. The remaining 52 substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that 26 substances [FLno: 15.038, 15.039, 15.044, 15.050, 15.051, 15.052, 15.058, 15.061, 15.062, 15.063, 15.067, 15.068, 15.069, 15.071, 15.078, 15.080, 15.082, 15.084, 15.085, 15.087, 15.089, 15.098, 15.108, 15.115, 15.116 and 15.118] do not give rise to safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. For the remaining 26 candidate substances 15.040, 15.042, 15.043, 15.045, 15.054, 15.055, 15.057, 15.064, 15.070, 15.072, 15.074, 15.076, 15.077, 15.079, 15.088, 15.091, 15.092, 15.093, 15.094, 15.096, 15.097, 15.106, 15.107, 15.129 and 15.135] evaluated through the Procedure, no appropriate NOAEL was available and additional data are required. Besides the safety assessment of these flavouring substances, the specifications for the In the present FGE.21Rev3, the 59 flavouring substances include five-and six-membered sulphurcontaining aromatic and non-aromatic heterocycles, which have been arranged into 11 subgroups in order to facilitate comparisons of the data sets between the groups. This division was done on the basis of degree of aromaticity and according to the presence of other heteroatoms (i.e. nitrogen). SUMMARYTwelve flavouring substances possess one or more chiral centres. For four of these substances 15.057, 15.079 and 15.135] the stereoisomeric composition has not been specified sufficiently.Forty-six of the flavouring substances are classified into structural class II and 13 candidate substances are classified into structural class III, according to the decision tree approach presented by Cramer et al., 1978. Forty-four candidate substances in the present group have been reported to occur in a wide range of food items.In its evaluation, the Panel as a default used the "Maximised Survey-derived Daily Intake" (MSDI) approach to estimate the per capita intakes of the flavouring substances in Europe. However, when the Panel examined the information provided by the European Flavour Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would grossly underestimate th...

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“…The final metabolite is subsequently excreted via urine, and may be converted spontaneously into 2-thienylmercapturic acid. (Dansette et al, 1992). The authors considered the formation of the epoxide intermediate, as suggested by Bray et al (1971), highly unlikely.…”

Section: ])mentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 21, Revision 2 (FGE.21Rev2): Thiazoles, thiophene, thiazoline and thienyl derivatives from chemical group 29. Miscellaneous substances from chemical group 30

Flavourings¹

2011

EFSA Journal

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The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 56 flavouring substances in the Flavouring Group Evaluation 21, Revision 2, using the Procedure in Commission Regulation (EC) No 1565/2000. Seven of the substances 15.086, 15.090, 15.099, 15.114, 15.119 and 15.133] were considered to have genotoxic potential. The remaining 49 substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that 26 substances 15.039, 15.044, 15.050, 15.051, 15.052, 15.058, 15.061, 15.062, 15.063, 15.067, 15.068, 15.069, 15.071, 15.078, 15.080, 15.082, 15.084, 15.085, 15.087, 15.089, 15.098, 15.108, 15.115, 15.116 and 15.118] do not give rise to safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. For the remaining 23 candidate substances 15.040, 15.042, 15.043, 15.045, 15.054, 15.055, 15.064, 15.070, 15.072, 15.074, 15.076, 15.077, 15.088, 15.091, 15.092, 15.093, 15.094, 15.096, 15.097, 15.106, 15.107 and 15.129], of the 49 substances evaluated through the Procedure, no appropriate NOAEL was available and additional data are required. Besides the safety assessment of these flavouring substances, the Flavouring Group Evaluation 21, Revision 2 2 EFSA Journal 2011; 9(10):1989 specifications for the materials of commerce have also been considered. For two substances are an identity test lacking and for one has the stereoisomeric composition to be specified. In the present FGE.21Rev2, the 56 candidate substances include five-and six-membered sulphurcontaining aromatic and non-aromatic heterocycles, which have been arranged into 11 subgroups in order to facilitate comparisons of the data sets between the groups. This division was done on the basis of degree of aromaticity and according to the presence of other heteroatoms (i.e. nitrogen).Five of the 56 candidate substances possess one chiral centre Forty-six of the 56 candidate substances are classified into structural class II and 10 candidate substances are classified into structural class III, according to the decision tree approach presented by Cramer et al., 1978. Forty-two of 56 the candidate substances have been reported to occur in a wide range of food items.In its evaluation, the Panel as a default used the "Maximised Survey-derived Daily Intake" (MSDI) approach to estimate the per capita intakes of the flavouring substances in Europe. However, when the Panel examined the information provided by the European Flavour Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would grossly underestimate the intake by regular consumers of products flavoured at the use level reported by the Industry, especially in those cases where the annual production values were reported to be small. ...

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Evidence for thiophene-s-oxide as a primary reactive metabolite of thiophene in vivo: Formation of a dihydrothiophene sulfoxide mercapturic acid

Cited by 73 publications

References 9 publications

Novel Metabolic Bioactivation Mechanism for a Series of Anti-Inflammatory Agents (2,5-Diaminothiophene Derivatives) Mediated by Cytochrome P450 Enzymes

Novel Metabolic Bioactivation Mechanism for a Series of Anti-Inflammatory Agents (2,5-Diaminothiophene Derivatives) Mediated by Cytochrome P450 Enzymes

Scientific Opinion on Flavouring Group Evaluation 21, Revision 3 (FGE.21Rev3): Thiazoles, thiophenes, thiazoline and thienyl derivatives from chemical groups 29 and 30

Scientific Opinion on Flavouring Group Evaluation 21, Revision 2 (FGE.21Rev2): Thiazoles, thiophene, thiazoline and thienyl derivatives from chemical group 29. Miscellaneous substances from chemical group 30

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