Identification of Metabolites of 4-Nonylphenol Isomer 4-(3′,6′-Dimethyl-3′-Heptyl) Phenol by Rat and Human Liver Microsomes

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Abstract
Nonylphenol (NP) has been widely used for more than 50 years in the synthesis of NP ethoxylates, which are important nonionic surfactants. NP is considered an endocrine disruptor based on in vitro and in vivo animal studies. However, the toxic effects of NP in humans are unknown. Information regarding the metabolic fate of 4-t-nonylphenol (4-tNP), a mixture of commercial NP branched isomers, in mammalian species is limited. This information is critical for the identification of adequate biomarkers of exposure to NP that could be used for exposure and risk assessment. We identified metabolites of one 4-tNP isomer, namely, 4-(3′,6′-dimethyl-3′-heptyl) phenol (P363-NP), using rat and human liver microsomes. The P363-NP metabolites were extracted by on-line solid-phase extraction and then separated and detected using high-performance liquid chromatography/tandem mass spectrometry. Using the genuine standard, we unambiguously identified 4-(3′,6′-dimethyl-3′-heptyl) catechol (P363-NC) as the main P363-NP metabolite when using human liver microsomes. Based on their chromatographic behavior and mass spectral fragmentation patterns, several other metabolites were tentatively identified, including a hydroxylated P363-NP with the alcohol functional group on the branched alkyl chain and its oxidative metabolite, a catechol with a hydroxylated alkyl side chain. Furthermore, the metabolite profile of P363-NP using rat and human enzymes was compared. Our findings suggest that P363-NC could be used as a biomarker to assess exposure to 4-tNP, although additional research to evaluate its suitability as a biomarker is warranted.