Induction of heme oxygenase in the small intestinal epithelium: a response to oral cadmium exposure.
The effects of oral cadmium administration on heme oxygenase activity and cytochrome P-450-dependent drug metabolism in intestinal epithelium were examined in male Sprague-Dawley rats. Cadmium chloride was administered via drinking water (0, 5 or 50 ppm cadmium) for 5 or 30 days, and heme oxygenase, 7-ethoxycoumarin O-deethylase (ECOD), 7-ethoxyresorufin O-deethylase (EROD) and cytochrome P-450 were measured in the liver and in the epithelium of the proximal region of the small intestine. Cadmium exposure produced a marked, dose-related induction of intestinal heme oxygenase (up to 300% of control levels) in the small intestine at both time points examined. Concomitant decreases in intestinal ECOD (70%) and EROD (65%) activities were also observed, with a 65% decline in cytochrome P-450 levels at 30 days as compared with controls. Oral cadmium exposure, however, did not affect heme catabolism or cytochrome P-450 function in the liver, even at the highest concentration (50 ppm) administered, although cadmium levels accumulated in a dose-related manner in the liver as well as in the small intestine. Systemic absorption of cadmium was limited, as reflected by the relatively low accumulation of cadmium in the liver at 5 days (approximately 20 micrograms/g), as compared with the levels present in small intestine at this time ponit (approximately 100 micrograms/g). These findings emphasize the sensitivity of cytochrome P-450-dependent drug metabolism in small intestinal epithelium to orally ingested cadmium, and highlight the vulnerability of this tissue to low-dose exposure to this metal.
Rosenberg
D W
DW
Rockefeller University, New York, NY 10021.
Kappas
A
A
D015660:7-Alkoxycoumarin O-Dealkylase / Q000096:biosynthesis; D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002104:Cadmium / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D019256:Cadmium Chloride; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D007421:Intestine, Small / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains
D002104:Cadmium; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D015660:7-Alkoxycoumarin O-Dealkylase; D019363:Cytochrome P-450 CYP1A1; D006419:Heme Oxygenase (Decyclizing); D019256:Cadmium Chloride