Control of Heme Oxygenase and Plasma Levels of Bilirubin by a Synthetic Heme Analogue, Tin-Protoporphyrin (original) (raw)
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Proceedings of the National Academy of Sciences, 1985
TinIV-protoporphyrin IX (Sn-protoporphyrin) potently inhibits heme degradation to bilirubin in vitro and in vivo, and it completely suppresses neonatal hyperbilirubinemia in experimental animals, including primates. It also reduces plasma bilirubin levels in certain naturally occurring or induced forms of jaundice in animals and man. We have examined in this study the fate of that fraction of heme whose degradation to bile pigment is inhibited in vivo by administration of this heme oxygenase (EC 1.14.99.3) inhibitor. In bile-duct-cannulated rats, infused exogenous heme is rapidly converted to biliary bilirubin; a small amount of the infused heme is excreted into bile as well. Sn-protoporphyrin, administered with the exogenous heme, markedly increased (3- to 4-fold) the amount of heme excreted into bile and greatly diminished biliary output of bilirubin. The increase in biliary heme output exceeded the decrease in bilirubin excretion elicited by the inhibitor metalloporphyrin. In the...
Journal of Clinical Investigation, 1985
The synthetic heme analogue Sn-protoporphyrin is a potent competitive inhibitor of heme oxygenase, the rate-limiting enzyme in heme degradation to bile pigment, and can entirely suppress hyperbilirubinemia in neonatal animals and significantly reduce plasma bilirubin levels in a variety of circumstances in experimental animals and man. To further explore the mechanism by which this metalloporphyrin reduces bilirubin levels in vivo, we have examined its effects on bilirubin production in bile duct-cannulated rats, in which bilirubin
The Effect of Tin (IV)-Protoporphyrin-IX on Bilirubin Production and Excretion in the Rat
Pediatric Research, 1987
ABSTRACI'. Tin (1V)-protoporphyrin-IXa (tin-heme) may have use in treating neonatal jaundice. To evaluate its effect on bilirubin metabolism, we measured bile-bilirubin excretion in adult, male Sprague-Dawley rats (350-500 g). After a 4-h baseline period, tin-heme (100 umol/kg) or buffer was injected subcutaneously, and bile was collected for 19 h. Bile flow, bile salt excretion, and bile-bilirubin excretion (averaging 600 f 60 ng/100 g/min for all animals) remained stable in the control period. Tin-heme treatment did not alter bile flow or bile salt excretion, but within 2 h bilirubin output was significantly reduced. The nadir of output was 5 h after injection when it was 380 Z 40 ng/ 100 g/min (p < 0.001). Cumulative excretion over 19 h was reduced 30.8% (p < 0.01). To determine if tin-heme
In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins
Journal of Perinatology, 2011
Objective: Neonatal jaundice results from an increased bilirubin production and decreased hepatic bilirubin conjugation and excretion. Severe hyperbilirubinemia is currently treated with phototherapy or exchange transfusion; however, its prevention by inhibiting bilirubin formation is a more logical strategy. Heme oxygenase (HO), with inducible (HO-1) and constitutive (HO-2) isoenzymes, is the rate-limiting enzyme in heme catabolism, producing equimolar amounts of bilirubin and carbon monoxide (CO). Metalloporphyrins (Mps) are heme derivatives that competitively inhibit HO and thereby suppress hyperbilirubinemia. No systematic studies have been reported evaluating whether the HO isoenzymes are inhibited differentially by various Mps. Identification of Mps that selectively inhibit the inducible HO-1 without affecting the 'housekeeping' HO-2 isoenzyme might be desirable in the clinical setting of hemolytic disease, in which the Hmox1 gene is greatly induced. Although bilirubin production is due to the activity of both HO-1 and HO-2, the inhibition of HO-1 with a relative sparing of HO-2 activity might provide the most selective approach for the treatment of hemolytic disease. Study Design: We determined for the deutero-, proto-, meso-and bisglycol porphyrins with zinc, tin and chromium as central atoms, respectively, the concentration needed for 50% inhibition (I 50) of HO-1 and HO-2 activities in rat spleen and brain tissue. Result: For a given Mp, HO-1 activity was less inhibited than that of HO-2. The order of inhibitor potency of each Mp was nearly identical for both isoenzymes. Tin mesoporphyrin was the most potent inhibitor for both isoenzymes. HO-2 selectivity was greatest for tin protoporphyrin. Conversely, the Zn compounds were least inhibitory toward HO-2. No Mp preferentially inhibited HO-1. Conclusion: Mps that produce a less inhibitory effect on HO-2, while limiting the response of the inducible HO-1, such as ZnPP, may be a useful clinical tool.
Journal of Clinical Investigation, 1985
Sn-protoporphyrin is a potent competitive inhibitor of heme oxygenase, the rate-limiting enzyme in heme degradation to bile pigment, and has been successfully utilized to suppress hyperbilirubinemia in a variety of experimental and naturally occurring forms of jaundice in animals and man. The compound is presumed to act in vivo primarily by inhibiting heme oxidation; thus it would be reasonable to expect that preservation of some functional moiety of cellular heme from degradation by heme oxygenase would occur after Sn-protoporphyrin administration. We have examined this question in liver by studying the heme saturation of tryptophan pyrrolase, the heme-dependent enzyme which controls the first and ratelimiting step in the catabolism of L-tryptophan. Sn-protoporphyrin, in doses (10 ;tmol/kg body wt) which entirely suppress neonatal hyperbilirubinemia in the experimental animal, leads to a very rapid ('30-60 min) increase in the heme saturation of tryptophan pyrrolase from normal levels of-50-60% to nearly 100%. The effect peaks at 1-2 h and lasts for at least 12 h. Sn-protoporphyrin is also able to block the rapid and marked decline in heme saturation of tryptophan pyrrolase elicited by inorganic cobalt, a potent inducer of heme oxygenase in liver. These findings establish clearly that after the administration of Sn-protoporphyrin in the whole animal, a functionally active heme pool, the one related to tryptophan pyrrolase, is rapidly increased in liver, confirming that the metalloporphyrin inhibits the degradation of endogenous heme by heme oxygenase.
Gut, 1990
Sn (tin4+)-protoporphyrin, a potent competitive inhibitor of haeme oxygenase, the rate limiting enzyme in the degradation of haeme to bile pigments, was given intravenously to six patients with primary biliary cirrhosis and to four patients with idiopathic haemochromatosis. Serum bilirubin concentrations decreased in all patients after administration of 1-2 tmollkg body weight of the metailoporphyrin, given in two doses eight to 24 hours apart. This reduction lasted approximately four to five days after injection of the compound. Excretion of endogenous haeme in bile increased (mean increase approximately two to threefold) in paraliel with the decrease in
Biochemical and Biophysical Research Communications, 1988
Heme oxygenase activities in human kidney microsomes were found to be from 0.238 to 0.620 nmol of bilirubin/mg/hr (mean 0.375, SD 0.134), which represent approximately 30% of activities determined for human adult liver. There was interindividual variation in heme oxygenase activity of a 2-5-fold difference. Rabbits were immunized with purified human liver heme oxygenase and the resulting antibody preparation was used to examine the species specificity of the enzyme. Microsomal protein with a molecular weight of 32,000 from human kidney was identified on Western blots by its reaction with the anti-heme oxygenase liver antibody similar to the purified enzyme protein. Thus, a homology exists between human hepatic and kidney heme oxygenase. The enzyme activity was sensitive to inhibition by metalloporphyrins, such as tin-protoporphyrin IX and, to a lesser degree, by zinc and cobalt protoporphyrin IX. In a study of different synthetic heme analogues for in vitro inhibition of heme oxygenase, we found that replacement of iron by zinc in deuteroporphyrin IX 2,4 bis glycol dramatically potentiated the inhibition of heme oxygenase activity. This finding demonstrated that zinc deuteroporphyrin IX 2,4 bis glycol is a most potent inhibitor of heme oxygenase activity. ©1908Academi cPr .... ~nc. Heme oxygenase is the enzyme responsible for the oxidative degradation of heme to the tetrapyrole biliverdin IX alpha. NADPH and molecular oxygen are required for this conversion. Biliverdin IX is then reduced to bilirubin IX by biliverdin reductase. Since heme oxygenase is the rate-limiting enzyme for heme degradation (1,2), it is evident that this enzyme is of great clinical importance. The activities of heme oxygenase are higher in those tissues normally involved in the destruction and breakdown of red blood cells, namely the spleen and the liver (1,3). Kidney heme oxygenase activity may play a significant role in the regulation of various hemoproteins subjected to enzyme induction by various inducers; the activity may increase lO0-fold in some hemolytic states in the kidney (4,5). A large number of heavy metals have been shown to induce heme oxygenase (6), leading to excess heme degradation and subsequent low levels of heme.
Proceedings of the National Academy of Sciences, 1981
The effects of various metalloporphyrins on hepatic heme oxygenase (EC 1.14.99.3) activity were examined in order to identify compounds that could inhibit heme degradation to bile pigment and might therefore be utilized to suppress the development of hyperbilirubinemia in the newborn. Among nine metal-protoporphyrin IX chelates (i.e., metal-hemes) studied, Sn-heme, Mn-heme, and Zn-heme substantially diminished heme oxygenase activity in vivo in the rat. These metalloporphyrins act as competitive inhibitory substrates in the heme oxygenase reaction but are not themselves oxidatively degraded. Sn-heme was the most potent enzyme inhibitor (Ki = 0.011 microM) in liver, spleen, kidney, and skin. Sn-heme administered to newborn animals within the first 72 hr after birth blocked the postnatal increase in heme oxygenase activity that occurs in various tissues. Its effect on the enzyme levels was prompt and protracted. Sn-heme administration also entirely prevented the development of hyperbi...