Regulation of intestinal cytochrome P-450 and heme by dietary nutrients. Critical role of selenium

The intestinal cytochrome P-450 (I-P-450)-dependent mixed function oxidase (MFO) system is regulated to a remarkable extent by various ingested xenobiotics, including drugs and carcinogens, as well as dietary nutrients. Accordingly, acute dietary iron deprivation is found to result in a marked decrease in I-P-450 content and activity. This decrease is most pronounced in the villous tip cells, the very cells committed to absorption of ingested materials. We investigated the mechanistic basis for such acute reduction and report that iron was not only required as a co-substrate for I-P-450 heme formation, but also as a regulator of two key heme-synthetic enzymes, delta-aminolevulinic acid synthetase and ferrochelatase. In addition, our studies revealed that dietary deprivation of selenium for a single day dramatically reduced I-P-450-dependent MFO activity. This prompt reduction apparently reflects impaired I-P-450 formation resulting from lowered ferrochelatase activity and consequently decreased intestinal heme availability, and was not a consequence of intracellular peroxidation presumably enhanced by concomitant lowering of the seleno-dependent glutathione peroxidase. Thus, we report the novel observation that dietary selenium also appears to be a critical modulator of intestinal cytochrome P-450-dependent metabolism of ingested drugs, carcinogens, and toxins that are absorbed by the intestinal mucosa.