XENOBIOTIC METABOLISM IN RAT, DOG, AND HUMAN PRECISION-CUT LIVER SLICES, FRESHLY ISOLATED HEPATOCYTES, AND VITRIFIED PRECISION-CUT LIVER SLICES

Human, rat, and dog phase I and phase II xenobiotic metabolism in prec ision-cut liver slices ana freshly isolated hepatocytes was compared u sing-a range of substrates, Carbamazepine (50 mu M) and styrene (2 mM) were used as probes to study the maintenance of cytochrome P450 and e poxide hydrolase-mediated metabolism in male Sprague-Dawley rat, preci sion-cut liver slices and hepatocytes. Carbamazepine. metabolism in bo th models resulted in the formation of the bioactive 10,11-epoxide (K- M = 766 mu M and V-max = 2.5 pmol/min/mg protein in precision-cut slic es). Epoxide formation was higher (2.4-fold) in hepatocytes than slice s. Styrene was deactivated to styrene diol at a higher rate in hepatoc ytes (9.7-fold) than slices, The lower rate of metabolism in slices co mpared with hepatocytes confirms our previous observations using testo sterone, 7-ethoxycoumarin, 1-chloro-2,4-dinitrobenzene and phosphorylo xyphenyl)-6-chloro-4-(3H)-quinazolinone in the rat. Testosterone 6 bet a-hydroxylation in human liver slices was similar to cultured hepatocy tes, but lower than in freshly isolated hepatocytes, 7-Ethoxycoumarin O-deethylation was higher in freshly isolated human hepatocytes, as wa s the ratio of glucuronide to 7-hydroxycoumarin. Testosterone hydroxyl ations, 7-ethoxycoumarin O-deethylation, and 1-chloro-2,4-dinitrobenze ne conjugation were also lower in male beagle dog slices, compared wit h freshly isolated hepatocytes. Attempts at long-term preservation of dog liver slices using vitrification and storage for up to 9 days at - 196 degrees C resulted in the retention of phase I and phase II metabo lism, although conjugation was lower than in freshly prepared slices. Xenobiotic metabolism in short-term incubations is consistently lower in dog and rat precision-cut slices than in freshly isolated hepatocyt es; whereas, in humans, this quantitative difference is partly hidden by the large interindividual variation.