INHIBITION AND INACTIVATION OF MURINE HEPATIC ETHOXYRESORUFIN AND PENTOXYRESORUFIN O-DEALKYLASE BY NATURALLY-OCCURRING COUMARINS

The present study was designed to evaluate the effects of a series of natural coumarins on ethoxyresorufin 0-dealkylase (EROD) and pentoxyre sorufin 0-dealkylase (PROD) activities in vitro using hepatic tissues from SENCAR mice. Fifteen different coumarins were examined for potent ial modulating activities. Several naturally occurring coumarins, foun d in the human diet, were effective inhibitors of hepatic EROD activit y in vitro, including coriandrin, bergamottin, isoimperatorin, and ost ruthin. Notably, coriandrin and bergamottin were approximately as pote nt as 7,8-benzoflavone, a relatively selective inhibitor of cytochrome P450 1A1. Several naturally occurring coumarins were also potent inhi bitors of hepatic PROD activity, including imperatorin, bergamottin, i sopimpinellin, and angelicin. Kinetic studies of the type of inhibitio n revealed that these compounds inhibited hepatic EROD and PROD activi ty by a variety of modes rather than by a uniform one. Furthermore, ex periments using a two-stage incubation assay revealed that coriandrin, imperatorin, ostruthin, and several other natural coumarins inactivat ed hepatic EROD activity (i.e., predominantly cytochrome P450 1A1-medi ated) and that isopimpinellin inactivated hepatic PROD activity (i.e., predominantly cytochrome P450 2B1-mediated). Finally, the results ind icate that some coumarins had selective inhibitory effects for EROD vs PROD and preliminary analyses suggested a possible structural basis f or the observed differences. The current data suggest that certain nat urally occurring coumarins, to which humans are exposed in the diet, a re potent modulators of cytochrome P450. Furthermore, these compounds may be capable of influencing the metabolic activation of other xenobi otics, including chemical carcinogens.