Microsomal metabolism of the terpene 1,8-cineole in the common brushtail possum (Trichosurus vulpecula), koala (Phascolarctos cinereus), rat and human

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 1,8-cineole intrinsic clearance (CL'_int = V_max/K_m in µl mg protein^-1 min^-1) was koala (188) > possum (181) >>rat (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 CL'_int of 1,8-cineole by brushtail possum liver microsomes (from 180 to 394µl mgprotein^-1 min^-1) and increased rat CL'_int by nearly 10-fold (from 28 to 259 µl mgprotein^-1 min^-1), but still less than the induced possum value. However, phenobarbitone had the greatest inducing effect, increasing the rat CL'_int to 1825µl mg protein^-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.