Abstract
We investigated the metabolic capabilities of C. elegans using compounds whose metabolism has been well characterised in mammalian systems. We find that similar metabolites are produced in C. elegans as in mammals but that C. elegans is deficient in CYP1-like metabolism, as has been seen in other studies. We show that CYP-34A9, CYP-34A10 and CYP-36A1 are the principal enzymes responsible for the metabolism of tolbutamide in C. elegans. These are related to the mammalian enzymes that metabolise this compound but are not the closest homologs suggesting that sequence comparison alone will not predict functional conservation among cytochrome P450s. In mammals, metabolite production from amytryptiline and dextromethorphan is dependent on specific cytochrome P450s. However, in C. elegans we did not find evidence of similar specificity: the same metabolites were produced but in small amounts by numerous cytochrome P450s. We conclude that, while some aspects of cytochrome P450 mediated metabolism in C. elegans are similar to mammals, there are differences in the production of some metabolites and in the underlying genetics of metabolism.
Highlights
Cytochrome P450s are enzymes with diverse and sometimes essential functions in organisms[1,2,3,4]
The production of carboxytolbutamide from tolbutamide and the production of paracetamol from phenacetin were only detected at levels close to the limit of quantification suggesting a metabolic deficiency in C. elegans versus mammals and relative to the other compounds tested
Tolbutamide metabolism to hydroxytolbutamide is affected by many cytochrome P450s but especially cyp-34A9, cyp-34A10 and cyp-36A1
Summary
Cytochrome P450s are enzymes with diverse and sometimes essential functions in organisms[1,2,3,4] They primarily catalyse oxidative reactions involving endogenous compounds such as lipids as well as exogenous and xenobiotic chemicals. They have been much studied in pharmaceutical research where they have been found to be important in drug metabolism[5]. Phase 1 metabolism results in the modification of the xenobiotic, commonly by hydroxylation catalysed by cytochrome P450 enzymes. Being critical to the first phase of xenobiotic and drug metabolism, cytochrome P450s have been extensively studied in mammalian systems whereby particular compounds have been identified as substrates for individual cytochrome P450s and the resulting metabolites identified[8,9]. Mammalian CYP450 required for metabolite production CYP1A2 CYP2C8/9/19 CYP2C8/9/19 CYP2C9 CYP2C19 CYP2D6 CYP2C19 CYP2D6 CYP3A4 CYP3A4
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