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
Autor: | Graham Ellis, Remo P. Badertscher, Andreas Natsch, Heike Laue, Susanne Kern |
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Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Time Factors Stereochemistry Toxicity test subchronic Coenzyme A Fragrance aldehyde Toxicology Benzoates Hydrocarbons Aromatic Risk Assessment 030226 pharmacology & pharmacy Rats Sprague-Dawley 03 medical and health sciences Acyl-CoA chemistry.chemical_compound 0302 clinical medicine Rat Sprague-Dawley Testis Animals Structure–activity relationship Benzoic acid Male reproductive toxicity Biotransformation Cells Cultured Aldehydes Molecular Structure Reproduction Toxicity Tests Subchronic Cell cultured Metabolism 660: Technische Chemie Perfume 030104 developmental biology chemistry Biochemistry Benzoyl-CoA Hepatocytes Xenobiotic Reproductive toxicity |
Zdroj: | Toxicological Sciences. 160:244-255 |
ISSN: | 1096-0929 1096-6080 |
DOI: | 10.1093/toxsci/kfx178 |
Popis: | Erworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch) 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. |
Databáze: | OpenAIRE |
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