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Xenobiotica

Title:		"Inhibition of the microsomal metabolism of 1,8-cineole in the common brushtail possum (Trichosurus vulpecula) by terpenes and other chemicals"
Author(s):		Pass GJ; McLean S;
Address:		"School of Pharmacy, University of Tasmania, Hobart 7001, Australia"
Journal Title:		Xenobiotica
Year:		2002
Volume:		32
Issue:		12
Page Number:		1109 - 1126
DOI:		10.1080/0049825021000022294
ISSN/ISBN:		0049-8254 (Print) 0049-8254 (Linking)
Abstract:		"1. Brushtail possums (Trichosurus vulpecula) ingest large amounts of terpenes in their diet of Eucalyptus leaf. Previously, we showed that dietary terpenes induce the cytochrome P450 enzymes (CYPs) responsible for their metabolism. The present study examined the effects of various CYP inhibitors on the metabolism of 1,8-cineole, the major dietary terpene, by liver microsomes from the possum and rat. 2. Ketoconazole inhibited the major reactions of terpene-induced microsomes in both species: 9-hydroxylation in the possum and 2-hydroxylation in the rat. This suggests the involvement of CYP3A enzymes, although in the possum there was a lack of the expected inhibition by troleandomycin or activation by alpha-naphthoflavone, highlighting the differences between species in CYP forms. Diethyldithiocarbamate also inhibited 9-hydroxylation in the possum, indicating that a CYP2E1-like enzyme contributes to this reaction. 3. Three other dietary terpenes were potent competitive inhibitors of 9-hydroxylation in the possum. K(i) ( micro M) (mean +/- SE, n = 4) were: alpha-pinene, 4.4 +/- 1.1; limonene, 7.8 +/- 2.1; p-cymene, 44.3 +/- 11.2; cuminyl alcohol (a p-cymene metabolite), 6.0 +/- 0.8. It appears likely that p-cymene acts via its metabolite to inhibit 1,8-cineole metabolism. 4. Inhibitory interactions between dietary terpenes, as well as other plant secondary compounds, may impose a significant constraint on foliage consumption in the common brushtail possum, therefore explaining the obligatory generalist nature of this browsing marsupial and other generalist herbivores"
Keywords:		"Animals Anti-Infective Agents, Local/pharmacology Aryl Hydrocarbon Hydroxylases/metabolism Cyclohexanols/antagonists & inhibitors/*metabolism Cytochrome P-450 CYP2E1/metabolism Cytochrome P-450 CYP3A Ditiocarb/pharmacology Dose-Response Relationship, Drug;"
Notes:		"MedlinePass, G J McLean, S eng England 2003/02/21 Xenobiotica. 2002 Dec; 32(12):1109-26. doi: 10.1080/0049825021000022294"