Cytochrome P450-dependent metabolic pathways and glucuronidation in trout liver slices.
We investigated the capacity of trout precision-cut liver slices to metabolize xenobiotics and steroids. As a first approach, liver slices were compared with freshly isolated trout hepatocytes, using 7-ethoxycoumarin (7-EC) and testosterone as substrates. Trout liver slices and freshly isolated hepatocytes had a similar capacity for conducting cytochrome P450-dependent metabolism, as indicated by the rate of oxidative metabolism of 7-EC and testosterone, and by the metabolic profile of these substrates. A lower rate of glucuronidation in slices compared with hepatocytes was observed with testosterone (50 microM), whereas the opposite situation occurred with 7-EC used at higher concentration (100 microM). In a second step, we investigated the effect of beta-naphthoflavone on 7-EC and testosterone biotransformation, using slices maintained in culture for 24 h, with or without the inducer added. The results were compared with the metabolic rates of these substrates incubated with liver slices originating from trout pretreated in vivo with beta-naphthoflavone. Cytochrome P450-mediated rates of 7-EC dealkylation and testosterone hydroxylation decreased to 38 and 55% of the control value, respectively, when incubations were performed in 24-h cultured slices instead of freshly cut slices. Exposure of the slices to 50 microM beta-naphthoflavone resulted in about 3 times higher deethylation rate of 7-EC. A similar value was obtained when treatment occurred in vivo. As demonstrated in rat by several authors, liver slices seem a useful and simple tool for studying the metabolic pathways of xenobiotics and steroids and for the assessment of inducers of the CYP1A1 family.
Cravedi
J P
JP
Laboratoire des Xénobiotiques, INRA, Toulouse, France.
Perdu-Durand
E
E
Paris
A
A
D000818:Animals; D001711:Biotransformation; D003374:Coumarins / Q000378:metabolism / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D017686:Oncorhynchus mykiss; D013739:Testosterone / Q000378:metabolism / Q000493:pharmacokinetics; D019324:beta-Naphthoflavone / Q000494:pharmacology