The in vitro and in vivo inhibition of intestinal heme oxygenase by tin-protoporphyrin.
The effects of tin-protoporphyrin (SnPP) on the activity of heme oxygenase in the epithelium of the proximal region of the small intestine were examined in male Sprague-Dawley rats. A single dose of SnPP (25 mumol/kg body weight) administered either parenterally or by gavage-produced time-dependent decreases in the activity of microsomal heme oxygenase over 24-48 h. Although heme oxygenase activity reverted to normal levels within 24 h after oral dosing, parenteral treatment resulted in substantial (70%) inhibition of the enzyme through at least 48 h after administration of the metalloporphyrin. In vitro, SnPP was shown to be a competitive inhibitor of microsomal heme oxygenase (Ki = 0.017 microM). Tissue tin levels were determined by graphite furnace atomic absorption spectroscopy 48 h after SnPP treatments. Comparable levels of tin were found in the liver and kidney after parenteral treatment (14.34 +/- 1.50 and 14.39 +/- 0.45 micrograms/g dry weight, respectively) while only 1.5-3% of these amounts were found in these organs after oral treatment with the metalloporphyrin. These studies establish that the rate-limiting enzyme in the catabolism of heme to bilirubin is inhibited in intestinal epithelium to the same extent as the enzyme is inhibited in other organs.
Rosenberg
D W
DW
Rockefeller University Hospital, New York, N.Y.
Drummond
G S
GS
Kappas
A
A
D000818:Animals; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D007422:Intestines / Q000201:enzymology; D008665:Metalloporphyrins / Q000494:pharmacology*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D011166:Porphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D014001:Tin / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution
D008665:Metalloporphyrins; D011166:Porphyrins; D011524:Protoporphyrins; D014001:Tin; C032628:tin protoporphyrin IX; D006899:Mixed Function Oxygenases; D006419:Heme Oxygenase (Decyclizing)