Cytochrome P450-catalysed arene-epoxidation of the bioactive tea tree oil ingredient p-cymene: Indication for the formation of a reactive allergenic intermediate?
Laboratories of Neuro-Oncology/Clinical and Cancer Proteomics, Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands. Xenobiotica
(Impact Factor: 2.2).
06/2009; 39(9):663-71. DOI: 10.1080/00498250902989094
1. The cytochrome P450-mediated metabolism of the tea tree oil ingredient p-cymene (p-isopropyltoluene) was studied by the application of in vitro enzymatic assays using different recombinant human cytochrome P450 enzymes. 2. In total, four enzymatic products were identified by gas chromatography-mass spectrometry. The enzymatic products identified were: thymol (2-isopropyl-5-methylphenol), p-isopropylbenzyl alcohol, p,alpha,alpha-trimethylbenzyl alcohol, and p-isopropylbenzaldehyde. 3. The enzymatic products of p-cymene resulted from catalysed enzymatic arene-epoxidation and hydroxylation reactions by the studied cytochrome P450 enzymes. 4. An in vivo study could only confirm the formation of one enzymatic product, namely thymol. Thymol was identified after enzymatic hydrolysis of glucuronide and sulphate conjugates in collected blood and urine samples. 5. The obtained results may help to increase the understanding of cases where skin sensitization and irritation by tea tree oil-containing products that are involved with allergic reactions of users of these products. The results also indicate that skin sensitization and irritation reactions not only can be explained by the frequently in literature reported auto-oxidation of tea tree resulting in bioactive oxidized products, but also now by the formation of epoxide intermediates resulting from catalysed arene-epoxidation reactions by selected human cytochrome P450 enzymes which are also located in different organs in humans.
Available from: nbn-resolving.de
Available from: Bernhard Wehrli
Available from: Marieta Elena Panait
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ABSTRACT: Thymus species have been used for centuries as a folk remedy against cancer.
The aim of the present study is to highlight some of the molecular mechanisms involved in
the anticancer properties of Thymus pulegioides L. The experiments were performed on
male Wistar rats, using the volatile oil from Thymus pulegioides L. The modifications of
cytochrome b5 content, cytochromes P450 content and activity, glutathione S-transferase
(GST), DT-diaphorase activity and glutathione (GSH) content were evaluated. GC-MS (gas
cromatography - mass spectrometry) analysis showed that the main components of Thymus
volatile oil were: carvacrol 17.92%, thymol 4.37% and germacrene D 9.84%. The positive
effects of Thymus volatile oil could be seen in modifications of the tumors volume and the
immune response. An increase was determined in the activity of phase II enzymes, GST and
DT-diaphorase, with 75% and 120% respectively. The most remarkable result of this study
is the difference in the macroscopic aspects of the tumors, following the administration of
Thymus volatile oil, which could recommend it as a chemopreventive agent.
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