Cytochrome P450-mediated metabolism in the human gut wall

Abstract

Objective Although the human small intestine serves primarily as an absorptive organ for nutrients and water, it also has the ability to metabolise drugs. Interest in the small intestine as a drug-metabolising organ has been increasing since the realisation that it is probably the most important extrahepatic site of drug biotransformation. Key findings Among the metabolising enzymes present in the small intestinal mucosa, the cytochromes P450 (CYPs) are of particular importance, being responsible for the majority of phase I drug metabolism reactions. Many drug interactions involving induction or inhibition of CYP enzymes, in particular CYP3A, have been proposed to occur substantially at the level of the intestine rather than exclusively within the liver, as originally thought. CYP3A and CYP2C represent the major intestinal CYPs, accounting for approximately 80% and 18%, respectively, of total immunoquantified CYPs. CYP2J2 is also consistently expressed in the human gut wall. In the case of CYP1A1, large interindividual variation in the expression levels has been reported. Data for the intestinal expression of the polymorphic CYP2D6 are conflicting. Several other CYPs, including the common hepatic isoform CYP2E1, are expressed in the human small intestine to only a very low extent, if at all. The distribution of most CYP enzymes is not uniform along the human gastrointestinal tract, being generally higher in the proximal regions of the small intestine. Summary This article reviews the current state of knowledge of CYP enzyme expression in human small intestine, the role of the gut wall in CYP-mediated metabolism, and how this metabolism limits the bioavailability of orally administered drugs. Possible interactions between drugs and CYP activity in the small intestine are also discussed.

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

“…Finally, rat CYP2J3, better known as the arachidonic acid epoxygenase (54), has shown very high 25-hydroxylase activities toward vitamin D 3 and is mostly expressed in the liver (31). CYP2J2, the human counterpart, is mainly involved in the cardiovascular system and intestinal metabolism of antihistamine drugs (55,56). Its 25-hydroxylase activity was much lower and seemed to favor vitamin D 2 over vitamin D 3 (57).…”

Carbon Monoxide–Bound Red Blood Cells Protect Red Blood Cell Transfusion-Induced Hepatic Cytochrome P450 Impairment in Hemorrhagic-Shock Rats

“…There is now a substantial body of evidence to support the notion that many of the pathophysiological events triggered by ischemia-reperfusion injury are mediated through the production of reactive oxygen species (ROS) and to the subsequent secretion of inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) (Carcillo et al, 2003). Previous studies clearly showed that these cytokines and ROS cause a decrease in P450 expression resulting from an enhancement in P450 degradation (Thelen and Dressman, 2009;Vee et al, 2009;Weaver, 2009). These findings led us to hypothesize that the reduction in P450 expression after RBC resuscitation may be caused by the degradation of P450 enzymes rather than the inhibition of P450 synthesis and that CO-RBC may inhibit P450 degradation via the suppression of ROS production or the expression of IL-6 and TNF-a, because it has been demonstrated that CO suppresses the production of both ROS and inflammatory cytokines (Motterlini and Otterbein, 2010).…”

Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

“…It should be noted that some caution must be applied when interpreting this data, as the in vitro experiments undertaken herein utilised transformed cell lines, which may not be fully representative of the in vivo tissue. However, we have selected those cell lines previously reported to be amongst the closest models of the relevant primary tissue (Lieber et al, 1976;Thelen and Dressman, 2009;Lin et al, 2012), which may mitigate this potential confounder to some degree.…”