METABOLISM OF COUMARIN AND 7-ETHOXYCOUMARIN BY RAT, MOUSE, GUINEA-PIG, CYNOMOLGUS MONKEY AND HUMAN PRECISION-CUT LIVER SLICES

1. The metabolism of 50 mu M 7-ethoxycoumarin and 50 mu M [3-C-14]coum arin has been studied in precision-cut liver slices from the male Spra gue-Dawley rat, female DBA/2 mouse, male Dunkin-Hartley guinea pig, ma le Cynomolgus monkey and man. 2. In liver slices from all five species 7-ethoxycoumarin was metabolized to 7-hydroxycoumarin (7-HC), which w as extensively conjugated with D -glucuronic acid and sulphate. In rat and mouse, 7-HC was preferentially conjugated with sulphate, whereas rates of glucuronidation and sulphation were similar in the other thre e species. 3. [3-C-14]coumarin was metabolized by liver slices from al l five species to various polar products and to metabolite(s) that bou nd covalently to liver slice proteins. In Cynomolgus monkey and both h uman subjects studied, 7-HC was the major metabolite that was conjugat ed with D-glucuronic acid and sulphate, whereas in rat the major metab olites were products of the S-hydroxylation pathway and unknown metabo lites. Major metabolites in mouse liver slices were 7-HC, 3-hydroxylat ion pathway products and unknown metabolites, and in guinea pig liver slices, 7-HC and unknown metabolites. 4. The metabolism of 7-ethoxycou marin to free and conjugated 7-HC and [3-C-14] coumarin to total polar products was greater in liver slices from mouse and Cynomolgus monkey than the other three species. 5. With liver slices from all five spec ies there appeared to be little difference in the extent of metabolism of 7-ethoxycoumarin and [3-C-14]coumarin to various products in eithe r a complex tissue culture medium (RPMI 1640 plus foetal calf serum) o r a simple balanced salt solution (Earle's balanced salt solution). 6. These results demonstrate that precision-cut liver slices are a valua ble in vitro model system for investigating species differences in xen obiotic metabolism. Generally, the observed species differences in cou marin metabolism in vitro agree well with available in vivo data.