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

Laue, Heike; Kern, Susanne; Badertscher, Remo P.; Ellis, Graham; Natsch, Andreas

doi:10.1093/toxsci/kfx178

Publication type:	Article in scientific journal
Type of review:	Peer review (publication)
Title:	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
Authors:	Laue, Heike Kern, Susanne Badertscher, Remo P. Ellis, Graham Natsch, Andreas
et. al:	No
DOI:	10.1093/toxsci/kfx178
Published in:	Toxicological Sciences
Volume(Issue):	160
Issue:	2
Page(s):	244
Pages to:	255
Issue Date:	1-Dec-2017
Publisher / Ed. Institution:	Oxford University Press
ISSN:	1096-0929 1096-6080
Language:	English
Subjects:	Acyl-CoA; Benzoic acid; Fragrance aldehyde; Male reproductive toxicity; Metabolism; Aldehydes; Benzoates; Biotransformation; Cell, cultured; Coenzyme A; Hepatocytes; Hydrocarbons, aromatic; Male; Molecular structure; Perfume; Rat, Sprague-Dawley; Reproduction; Risk assessment; Testis; Toxicity test, subchronic
Subject (DDC):	660: Chemical engineering
Abstract:	Several 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.
Further description:	Erworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch)
URI:	https://digitalcollection.zhaw.ch/handle/11475/23925
Fulltext version:	Published version
License (according to publishing contract):	Licence according to publishing contract
Departement:	Life Sciences and Facility Management
Organisational Unit:	Institute of Chemistry and Biotechnology (ICBT)
Appears in collections:	Publikationen Life Sciences und Facility Management

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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.