Microsomal metabolism of the terpene 1,8-cineole in the common brushtail possum (Trichosurus vulpecula), koala (Phascolarctos cinereus), rat and human
G. J. PASS1, S. MCLEAN1 I. STUPANS3 and N. DAVIES2
1School of Pharmacy and
2Central Science Laboratory, University of Tasmania, Hobart 7001, Australia
3School of Pharmacy and Medical Sciences, University of South Australia, Adelaide 5000, Australia
1. This study reports on the pathways of metabolism and enzyme kinetics of the Eucalyptus terpene, 1,8-cineole, by liver microsomes from the brushtail possum (Trichosurus vulpecula) and koala (Phascolarctos cinereus) (animals that normally include this terpene in their diet), rat and human.
2. The rank order of the ability to metabolize 1,8-cineole with respect to overall 1,8cineole intrinsic clearance (CL0int ˆ Vmax=Km inmlmgprotein 1 min 1) was koala (188)> possum (181)¾rat (28)> human (12). This order supports the hypothesis that adaptation to a Eucalyptus diet involves enhanced metabolism of terpenes.
3. The metabolism of 1,8-cineole was also studied in the liver from brushtail possum pretreated with a mixture of terpenes, which have previously been shown to induce cytochrome P450 enzymes. Rats were pretreated with the same mixture of terpenes or phenobarbitone.
4. Terpene pretreatment more than doubled the CL0int of 1,8-cineole by brushtail possum livermicrosomes(from 180 to394mlmgprotein 1 min 1)andincreasedratCL0int by nearly 10-fold (from 28 to 259mlmgprotein 1 min 1), but still less than the induced possum value. However, phenobarbitone had the greatest inducing e ect, increasing the rat CL0int to 1825mlmgprotein 1 min 1.
5. A regioselective preference of oxidation was evident between adapted and nonadapted species. In rat and human oxidation was preferred at the aliphatic ring carbons over methyl substituents. In possum, many of the available carbons were utilized, however metabolism at methyl substituents was preferred. In the koala, oxidation occurred primarily at the methyl substituents.