Effects of mammalian CYP3A inducers on CYP3A-related enzyme activities in grass carp (Ctenopharyngodon idellus): Possible implications for the establishment of a fish CYP3A induction model

摘要

Unexpected drug–drug interactions in fish are generally associated with the induction of CYP3A activity and may lead to the formation of drug residues and thus threaten the safety of fishery products. However, little information is available about CYP3A induction in fish. In the present study, we determined the in vivo and in vitro effects of typical mammalian CYP3A inducers (rifampicin, phenobarbital and dexamethasone) on CYP3A-related enzyme activities in a freshwater teleost, the grass carp (Ctenopharyngodon idellus). Our results showed that the response to rifampicin was similar for grass carp liver cell line (GCL), liver microsomes and the primary hepatocytes of grass carp, as indicated by the activity of aminopyrine N-demethylase (APND). When erythromycin N-demethylase (ERND) and 6β-testosterone hydroxylase (6β-TOH) were taken into consideration, the GCL displayed a greater capacity for conducting CYP3A metabolism and induction than the C. idellus kidney cell line (CIK). Using erythromycin and testosterone as substrates, we demonstrated that CYP3A catalysis exhibited non-Michaelis-Menten kinetics in GCL cells, and that Vmax/Km values were significantly increased due to rifampicin-treatment. Overall, this study may have implications for the use of GCL as a CYP3A induction model to identify physiological changes in fish as well as the similarities or differences between fish and mammals.