The small intestine as a xenobiotic-metabolizing organ.

The mammalian small intestine serves principally as the site for absorption of nutrients, water, and both beneficial and potentially harmful xenobiotics. However, it has become apparent over the past 20 years, and most notably during the past 10 years, that an array of metabolic machinery is also expressed in this organ (Kaminsky and Fasco, 1992; Lin et al., 1999; Doherty and Charman, 2002; Ding and Kaminsky, 2003). Both phase I and phase II metabolic enzymes are expressed, together with associated transporters. In this minireview we discuss some of the most prominent phase I and II enzymes in the metabolic systems in the small intestine. The transporters, despite their importance for the fate of enterocyteabsorbed xenobiotics, are beyond the scope of this minireview (Suzuki and Sugiyama, 2000). The morphology of the small intestine plays a major role in this organ’s metabolic competency, with several anatomic and physiologic features contributing. Among these are: the considerable length of the small intestine (7 m in humans and 90 cm in the rat) (Iatropoulos, 1986) divided proximally to distally into the duodenum, jejunum, and ileum; the distribution of the metabolically competent epithelium as a monolayer of enterocytes; and the amplification of the lumenal surface of the small intestine by numerous finger-like projections of enterocyte-lined villi and, at their bases, buried crypts. Together these features provide an expansive surface for xenobiotic absorption, with a consequent substantial potential for first-pass metabolism. Enterocytes have a very limited life span; after the division of stem cells in the crypt base, migration up to the crypt surface in humans takes 4 days and in rodents, 3 days. The cells then migrate to the villous tip, where they are sloughed off and excreted, a passage of 3 days in humans and 2 days in rodents (Iatropolous, 1986). The shortness of the enterocyte life span diminishes the potential of metabolic enzymeinducing agents in the small intestine to produce increased metabolic rates in the enterocytes for an extended length of time. Additionally, any lesions produced by covalent binding of bioactivated xenobiotics to enterocyte macromolecules will be short-lived, as a consequence of the sloughing off and excretion of the affected enterocytes. Hypotheses that the small intestine plays an important role in first-pass metabolism of orally ingested xenobiotics are supported by the expression of numerous metabolic enzymes in the organ, the positioning of the small intestine as the first site of exposure of xenobiotics to metabolic systems, and the large surface area available in the small intestine for absorption of the xenobiotics. However, in humans, assessments of the relative contributions of the liver and small intestine to first-pass metabolism of xenobiotics have been difficult to make. It has been suggested that a deeper understanding must await the successful development of methods to decouple hepatic and small intestinal first-pass metabolism (Doherty and Charman, 2002). Two recent reviews have focused on the relative importance of the small intestine and the liver for first-pass metabolism (Lin et al., 1999; Doherty and Charman, 2002). The authors suggested that the greater overall weight of the human liver ( 1.5 kg) relative to that of the small intestine ( 0.7 kg), which when combined with the P450 concentrations and the microsomal protein contents provide for a greater overall metabolic capacity for the liver, and the potential of absorbed systemic xenobiotics to undergo countercurrent exchange (diffusion from intestinal villous arterioles to venules without access to the enterocytes), would strongly favor the liver (Lin et al., 1999). The possibly greater role of the liver than the small intestine in first-pass metabolism does not, however, detract from the capability of the small intestine to directly metabolize orally ingested xenobiotics prior to systemic uptake, and thus to block uptake. A reoccurring theme from studies of human small intestinal xenobiotic metabolism is the interindividual variability in expression of phase I and II metabolic enzymes, frequently in marked excess of the variability of the same enzymes in the liver (Paine et al., 1997; Strassburg et al., 2000). Although known polymorphisms in the coding and noncoding regions of the relevant genes could account for some of the variability in enzyme activity and expression, this is unlikely to differentially affect the small intestine and liver. The mechanisms for the small intestinal variability in expression are not known. A possible contributor could reside in the genesis of the villous columnar enterocytes. The enterocytes are derived from multipotent stem cells that reside in the crypts. The enterocytes, which form columns on each villus, can be derived from more than one crypt stem cell, each with differing levels of expression of a particular gene (Wong et al., 2000). The possibility of this being a factor in interindividual variability in small intestinal metabolic enzyme expression awaits further study. Another possibility is that the intestinal P450s have been differentially induced in different individuals by dietary and environmental factors. CYP3A4 has, in fact, been demonstrated to be induced in human small intestine by rifampicin (Kolars et al., 1992). This work was supported in part by Grant R827180010 from the United States Environmental Protection Agency. It has not been subjected to the Agency’s required peer and policy review, and therefore, does not necessarily reflect the views of the agency, and no official endorsement should be inferred.