Cytochrome P450s (hereafter, CYPs) are a broad class of enzymes largely responsible for drug metabolism. Preclinical drug discovery programs monitor drug metabolism by CYP enzymes in a variety of model species to ensure that drugs are circulating at safe and therapeutic levels. Different species, however, possess CYPs with varying affinities for substrates and therefore metabolize drugs at different rates. This is a potential problem for the translation of preclinical data to predict the effect of drugs in humans and non-model systems. The aim of this study was to measure the activity of CYPs isolated from multiple species to metabolize standard CYP substrates and natural products from plants being developed as potential drugs. We hypothesized that laboratory-bred species would have faster rates of metabolism for standard substrates than domestic or wild species and that wild species that naturally consume plants would have faster rates of metabolism of natural products from plants. Gas chromatography was used to measure metabolism of volatile natural products by nonspecific CYPs, and a bioluminescence assay was used to measure metabolism of standard substrates by two specific CYPs. The rate of substrate loss or formation of metabolites was compared among species using an ANOVA. Variation was observed among species for degradation of standard substrates and natural products, and rates for a specific substrate differed for different CYP enzymes. These <i>in vitro </i>data will be used to interpret <i>in vivo</i> studies to translate rates of metabolism of existing and newly developed drugs in model species to predict their metabolism in humans, domestic and wild species.

Species differences in detoxification rates

249th National Meeting (2015)

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