Inhibition and inactivation of murine hepatic ethoxy- and pentoxyresorufin O-dealkylase by naturally occurring coumarins

Abstract

The present study was designed to evaluate the effects of a series of natural coumarins on ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities in vitro using hepatic tissues from SENCAR mice. Fifteen different coumarins were examined for potential modulating activities. Several naturally occurring coumarins, found in the human diet, were effective inhibitors of hepatic EROD activity in vitro, including coriandrin, bergamottin, isoimperatorin, and ostruthin. Notably, coriandrin and bergamottin were approximately as potent as 7,8-benzoflavone, a relatively selective inhibitor of cytochrome P450 1A1. Several naturally occurring coumarins were also potent inhibitors of hepatic PROD activity, including imperatorin, bergamottin, isopimpinellin, and angelicin. Kinetic studies of the type of inhibition revealed that these compounds inhibited hepatic EROD and PROD activity by a variety of modes rather than by a uniform one. Furthermore, experiments using a two-stage incubation assay revealed that coriandrin, imperatorin, ostruthin, and several other natural coumarins inactivated hepatic EROD activity (i.e., predominantly cytochrome P450 1A1-mediated) and that isopimpinellin inactivated hepatic PROD activity (i.e., predominantly cytochrome P450 2B1-mediated). Finally, the results indicate that some coumarins had selective inhibitory effects for EROD vs PROD and preliminary analyses suggested a possible structural basis for the observed differences. The current data suggest that certain naturally occurring coumarins, to which humans are exposed in the diet, are potent modulators of cytochrome P450. Furthermore, these compounds may be capable of influencing the metabolic activation of other xenobiotics, including chemical carcinogens.

Metabolism of Bergamottin by Cytochromes P450 2B6 and 3A5

“…This observation supports previous studies that indicated that inactivation of P450 enzymes by psoralens required the presence of the furan ring double bond (Letteron et al, 1986;Cai et al, 1993). Tandem mass analysis of the glutathione conjugates of BG formed by P450 2B6 resulted in fragments that were most consistent with GS adduction to the furan ring analogous to what has been observed with 8-methoxypsoralen and P450 2B1 (Koenigs and Trager, 1998).…”

Imperatorin Is a Mechanism-Based Inactivator of CYP2B6

“…Angelicin, isopimpinellin, 8-methoxypsoralen, psoralen, isopsoralen, bergamottin, and other related compounds in this family have shown inhibitory effects on CYP1A1, CYP1A2, CYP2B6, CYP3A4, and CYP3A5 (Baumgart et al, 2005;Lin et al, 2005;Zhuang et al, 2013). In addition, several furanocoumarin compounds in umbelliferous vegetables, such as 8-methoxypsoralen, bergapten, and isopimpinellin, have been found to be the mechanism-based inactivators of CYP2B1 (Cai et al, 1993;Koenigs and Trager, 1998). We speculated that IMP may show a similar irreversible inhibitory effect on the CYP2B subfamily.…”

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

“…However, in HLMs, time-dependent CYP1A2 inhibition was only observed with the angular furanocoumarin, IPRN. This difference may be attributed to that difference in compounds although they are in the same class, different enzymes and probe P450 substrate specificity (Cai et al, 1993, Paine et al, 2004Prince et al, 2006). It remains to be seen whether the angular furanocoumarins are generally more prone to the formation of more reactive epoxide metabolites, similar to the well established Bay Region theory of polyaromatic hydrocarbons (Lehr and Jerina, 1977;Chang et al, 2013).…”