In Vitro Hepatic Assessment of Cineole and Its Derivatives in Common Brushtail Possums (Trichosurus vulpecula) and Rodents

SIMPLE SUMMARY: Folivore marsupials can metabolise high levels of dietary terpenes compared to eutherian mammals, indicating that they possess highly efficient drug metabolising enzymes. However, two such highly efficient drug metabolising enzymes, cytochrome P450 3A and UDP-glucuronosyltransferase, are involved in terpene metabolism, evidence for inhibitory actions by these dietary terpenes on these enzymes are limited. Therefore, we investigated the effect of cineole, a major component of eucalyptus essential oils, and its derivatives on these hepatic drug metabolising enzymes in mice, rats, and possums. Our findings revealed no major inhibition on these drug metabolising enzymes by cineole and its derivatives at concentrations up to 50 µM. However, species-specific difference in their basal enzymatic activity was observed and may provide an avenue for developing future pest control strategies. ABSTRACT: Folivore marsupials, such as brushtail possum (Trichosurus Vulpecula) and koala (Phascolarctos cinereus), can metabolise higher levels of dietary terpenes, such as cineole, that are toxic to eutherian mammals. While the highly efficient drug metabolising enzymes, cytochrome P450 3A (CYP3A) and phase II conjugating enzymes (UDP-glucuronosyltransferase, UGT), are involved in the metabolism of high levels of dietary terpenes, evidence for inhibitory actions on these enzymes by these terpenes is scant. Thus, this study investigated the effect of cineole and its derivatives on catalytic activities of hepatic CYP3A and UGT in mice, rats, and possums. Results showed that cineole (up to 50 µM) and its derivatives (up to 25 µM) did not significantly inhibit CYP3A and UGT activities in mice, rats, and possums (both in silico and in vitro). Interestingly, basal hepatic CYP3A catalytic activity in the possums was ~20% lower than that in rats and mice. In contrast, possums had ~2-fold higher UGT catalytic activity when compared to mice and rats. Thus, these basal enzymatic differences may be further exploited in future pest management strategies.