Oxidative metabolism of foreign compounds in rat small intestine: cellular localization and dependence on dietary iron.

Oxidative metabolism of foreign compounds was measured in the intestinal mucosa of male rats. Activities of benzpyrene hydroxylase, p-nitroanisole O-demethylase, and NADPH-cytochrome P-450 reductase and cytochrome P-450 content were 3 to 10 times higher in epithelial cells of the upper villus than in mucosal crypt cells. Villous tip cells of the upper small intestine exhibited much higher cytochrome P-450 content and drug-metabolizing enzyme activity than did tip cells of lower intestinal segments. In rats fed commercial chow diet, cytochrome P-450 content and drug-metabolizing enzyme activity in villous tip cells of duodenal mucosa were higher than in animals fed a semisynthetic diet, but cytochrome b5 and NADPH-cytochrome P-450 reductase were unaffected. On restriction of dietary iron intake, cytochrome P-450 and oxidative enzyme activity fell sharply, but were completely restored in 24 hr by oral iron supplementation, whereas parenteral iron administration was ineffective. These findings suggest that intestinal drug metabolism is localized primarily in the upper villous cells of the proximal intestinal mucosa, that cytochrome P-450 is synthesized in maturing epithelial cells as they migrate from the crypts to the tip of the mucosal villi, and that this process is dependent critically upon absorption of iron from the intestinal lumen.

Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase.

Hemoglobin and myoglobin are a major source of dietary iron in man. Heme, separated from these hemoproteins by intraluminal proteolysis, is absorbed intact by the intestinal mucosa. The absorbed heme is cleaved in the mucosal cell releasing inorganic iron. Although this mucosal heme-splitting activity initially was ascribed to xanthine oxidase, we investigated the possibility that it is catalyzed by microsomal heme oxygenase, an enzyme which converts heme to bilirubin, CO, and inorganic iron. Microsomes prepared from rat intestinal mucosa contain enzymatic activity similar to that of heme oxygenase in liver and spleen. The intestinal enzyme requires NADPH; is completely inhibited by 50% CO; and produces bilirubin IX-alpha, identified spectrophotometrically and chromatographically. Moreover, duodenal heme oxygenase was shown to release inorganic (55)Fe from (55)Fe-heme. Along the intestinal tract, enzyme activity was found to be highest in the duodenum where hemoglobin iron absorption is reported to be most active. Furthermore, when rats were made iron deficient, duodenal heme oxygenase activity and hemoglobin-iron absorption rose to a comparable extent. Upon iron repletion of iron-deficient animals, duodenal enzyme activity returned towards control values. In contrast to heme oxygenase, duodenal xanthine oxidase activity fell sharply in iron deficiency and rose towards base line upon iron repletion. Our findings suggest that mucosal heme oxygenase catalyzes the cleavage of heme absorbed in the intestinal mucosa and thus plays an important role in the absorption of hemoglobin iron. The mechanisms controlling this intestinal enzyme activity and the enzyme's role in the overall regulation of hemoglobin-iron absorption remain to be defined.