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dc.contributor.authorLaue, Heike-
dc.contributor.authorKern, Susanne-
dc.contributor.authorBadertscher, Remo P.-
dc.contributor.authorEllis, Graham-
dc.contributor.authorNatsch, Andreas-
dc.date.accessioned2022-01-14T13:37:00Z-
dc.date.available2022-01-14T13:37:00Z-
dc.date.issued2017-12-01-
dc.identifier.issn1096-0929de_CH
dc.identifier.issn1096-6080de_CH
dc.identifier.urihttps://digitalcollection.zhaw.ch/handle/11475/23925-
dc.descriptionErworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch)de_CH
dc.description.abstractSeveral aromatic aldehydes such as 3-(4-tert-butylphenyl)-2-methylpropanal were shown to adversely affect the reproductive system in male rats following oral gavage dose of ≥ 25 mg/kg bw/d. It was hypothesized that these aldehydes are metabolized to benzoic acids such as p-tert-butylbenzoic acid as key toxic principle and that Coenzyme A (CoA) conjugates may be formed from such acids. Here we performed a detailed structure activity relationship study on the formation of benzoic acids from p-alkyl-phenylpropanals and related chemicals in rat hepatocytes in suspension. Formation of CoA conjugates from either p-alkyl-phenylpropanals directly or from their benzoic acid metabolites was further assessed in plated rat hepatocytes using high resolution LC-MS. All of the test chemicals causing reproductive adverse effects in male rats formed p-alkyl-benzoic acids in rat hepatocytes in suspension. Compounds metabolized to p-alkyl-benzoic acids led to accumulation of p-alkyl-benzoyl-CoA conjugates at high and steady levels in plated rat hepatocytes, whereas CoA conjugates of most other xenobiotic acids were only transiently detected in this in vitro system. The correlation between this metabolic fate and the toxic outcome may indicate that accumulation of the alkyl-benzoyl-CoA conjugates in testicular cells could impair male reproduction by adversely affecting CoA-dependent processes required for spermatogenesis. This hypothesis prompted a search for new p-alkyl-phenylpropanal derivatives which do not form benzoic acid metabolites and the corresponding CoA conjugates. It was found that such metabolism did not occur with a derivative containing an o-methyl substituent, ie, 3-(4-isobutyl-2-methylphenyl)propanal. This congener preserved the fragrance quality but lacked the male reproductive toxicity in a 28-day rat study, as predicted from its in vitro metabolism.de_CH
dc.language.isoende_CH
dc.publisherOxford University Pressde_CH
dc.relation.ispartofToxicological Sciencesde_CH
dc.rightsLicence according to publishing contractde_CH
dc.subjectAcyl-CoAde_CH
dc.subjectBenzoic acidde_CH
dc.subjectFragrance aldehydede_CH
dc.subjectMale reproductive toxicityde_CH
dc.subjectMetabolismde_CH
dc.subjectAldehydesde_CH
dc.subjectBenzoatesde_CH
dc.subjectBiotransformationde_CH
dc.subjectCell, culturedde_CH
dc.subjectCoenzyme Ade_CH
dc.subjectHepatocytesde_CH
dc.subjectHydrocarbons, aromaticde_CH
dc.subjectMalede_CH
dc.subjectMolecular structurede_CH
dc.subjectPerfumede_CH
dc.subjectRat, Sprague-Dawleyde_CH
dc.subjectReproductionde_CH
dc.subjectRisk assessmentde_CH
dc.subjectTestisde_CH
dc.subjectToxicity test, subchronicde_CH
dc.subject.ddc660: Technische Chemiede_CH
dc.titlep-alkyl-benzoyl-CoA conjugates as relevant metabolites of aromatic aldehydes with rat testicular toxicity-studies leading to the design of a safer new fragrance chemicalde_CH
dc.typeBeitrag in wissenschaftlicher Zeitschriftde_CH
dcterms.typeTextde_CH
zhaw.departementLife Sciences und Facility Managementde_CH
zhaw.organisationalunitInstitut für Chemie und Biotechnologie (ICBT)de_CH
dc.identifier.doi10.1093/toxsci/kfx178de_CH
dc.identifier.pmid28973542de_CH
zhaw.funding.euNode_CH
zhaw.issue2de_CH
zhaw.originated.zhawNode_CH
zhaw.pages.end255de_CH
zhaw.pages.start244de_CH
zhaw.publication.statuspublishedVersionde_CH
zhaw.volume160de_CH
zhaw.publication.reviewPeer review (Publikation)de_CH
zhaw.author.additionalNode_CH
zhaw.display.portraitYesde_CH
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Laue, H., Kern, S., Badertscher, R. P., Ellis, G., & Natsch, A. (2017). p-alkyl-benzoyl-CoA conjugates as relevant metabolites of aromatic aldehydes with rat testicular toxicity-studies leading to the design of a safer new fragrance chemical. Toxicological Sciences, 160(2), 244–255. https://doi.org/10.1093/toxsci/kfx178
Laue, H. et al. (2017) ‘p-alkyl-benzoyl-CoA conjugates as relevant metabolites of aromatic aldehydes with rat testicular toxicity-studies leading to the design of a safer new fragrance chemical’, Toxicological Sciences, 160(2), pp. 244–255. Available at: https://doi.org/10.1093/toxsci/kfx178.
H. Laue, S. Kern, R. P. Badertscher, G. Ellis, and A. Natsch, “p-alkyl-benzoyl-CoA conjugates as relevant metabolites of aromatic aldehydes with rat testicular toxicity-studies leading to the design of a safer new fragrance chemical,” Toxicological Sciences, vol. 160, no. 2, pp. 244–255, Dec. 2017, doi: 10.1093/toxsci/kfx178.
LAUE, Heike, Susanne KERN, Remo P. BADERTSCHER, Graham ELLIS und Andreas NATSCH, 2017. p-alkyl-benzoyl-CoA conjugates as relevant metabolites of aromatic aldehydes with rat testicular toxicity-studies leading to the design of a safer new fragrance chemical. Toxicological Sciences. 1 Dezember 2017. Bd. 160, Nr. 2, S. 244–255. DOI 10.1093/toxsci/kfx178
Laue, Heike, Susanne Kern, Remo P. Badertscher, Graham Ellis, and Andreas Natsch. 2017. “P-Alkyl-Benzoyl-CoA Conjugates as Relevant Metabolites of Aromatic Aldehydes with Rat Testicular Toxicity-Studies Leading to the Design of a Safer New Fragrance Chemical.” Toxicological Sciences 160 (2): 244–55. https://doi.org/10.1093/toxsci/kfx178.
Laue, Heike, et al. “P-Alkyl-Benzoyl-CoA Conjugates as Relevant Metabolites of Aromatic Aldehydes with Rat Testicular Toxicity-Studies Leading to the Design of a Safer New Fragrance Chemical.” Toxicological Sciences, vol. 160, no. 2, Dec. 2017, pp. 244–55, https://doi.org/10.1093/toxsci/kfx178.


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