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In recent years concerns over consumer exposure to mineral oil aromatic hydrocarbons (MOAH), especially those containing alkylated polycyclic aromatic hydrocarbons (PAHs), have emerged. This is especially due to the fact that some PAHs are known to be genotoxic and carcinogenic upon metabolic activation. However, available toxicological data on PAHs mainly relate to non-substituted PAHs with limited data on alkyl substituted PAHs. Therefore, the aim of the present study was to characterize in more detail the effect of alkyl substitution on the metabolism and mutagenicity of benzo[ a ]pyrene (B[ a ]P), a PAH known to be genotoxic and carcinogenic. To this end, the oxidative metabolism and mutagenicity of B[ a ]P and a series of its alkyl substituted analogues were quantified using in vitro microsomal incubations and the Ames test. The results obtained reveal that upon alkylation the metabolic oxidation shifts to the aliphatic side chain at the expense of aromatic ring oxidation. The overall metabolism, including metabolism via aromatic ring oxidation resulting potentially in bioactivation, was substantially reduced with elongation of the alkyl side chain, with metabolism of B[ a ]P with an alkyl substituent of >6 C atoms being seriously hampered. In the Ames test upon metabolic activation, the methyl substitution of B[ a ]P resulted in an increase or decrease of the mutagenic potency depending on the substitution position. The relevant pathways for mutagenicity of the selected monomethyl substituted B[ a ]P may involve the formation of a 7,8-dihydrodiol-9,10-epoxide, a 4,5-oxide and/or a benzylic alcohol as an oxidative side chain metabolite which subsequently may give rise to an unstable and reactive sulfate ester conjugate. It is concluded that alkylation of B[ a ]P does not systematically reduce its mutagenicity in spite of the metabolic shift from aromatic to side chain oxidation. • Methylation of B[ a ]P shifts the metabolism to alkyl oxidation. • Methylation of B[ a ]P alters the mutagenic potency upon bioactivation in Ames test. • Mutagenic potency of methyl-B[ a ]P depends on substitution position and tester strain. • Alkylation of B[ a ]P does not systematically reduce its mutagenicity. [ABSTRACT FROM AUTHOR]

Mineral oils are widely applied in food production and processing and may contain polycyclic aromatic hydrocarbons (PAHs). The PAHs that may be present in mineral oils are typically alkylated, and have been barely studied. Metabolic oxidation of the aromatic ring is a key step to form DNA-reactive PAH metabolites, but may be less prominent for alkylated PAHs since alkyl substituents would facilitate side chain oxidation as an alternative. The current study investigates this hypothesis of preferential side chain oxidation at the cost of aromatic oxidation using naphthalene and a series of its alkyl substituted analogues as model compounds. The metabolism was assessed by measuring metabolite formation in rat and human liver microsomal incubations using UPLC and GC-MS/MS. The presence of an alkyl side chain markedly reduced aromatic oxidation for all alkyl-substituted naphthalenes that were converted. 1-n-Dodecyl-naphthalene was not metabolized under the experimental conditions applied. With rat liver microsomes for 1-methyl-, 2-methyl-, 1-ethyl-, and 2-ethyl- naphthalene, alkyl side chain oxidation was preferred over aromatic oxidation. With human liver microsomes this was the case for 2-methyl-, and 2-ethyl-naphthalene. It is concluded that addition of an alkyl substituent in naphthalene shifts metabolism in favor of alkyl side chain oxidation at the cost of aromatic ring oxidation. Furthermore, alkyl side chains of 6 or more carbon atoms appeared to seriously hamper and reduce overall metabolism, metabolic conversion being no longer observed with the C12 alkyl side chain. In summary, alkylation of PAHs likely reduces their chances of aromatic oxidation and bioactivation. • Alkyl substitution of naphthalene shifts metabolism in favor of alkyl side chain oxidation at the cost of aromatic ring oxidation. • Metabolism and bioactivation of naphthalene is hampered when the alkyl substituent contains over 6 carbon atoms. • Alkylation of PAHs likely reduces their chances on aromatic oxidation and potential bioactivation. [ABSTRACT FROM AUTHOR]