Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tin greatly enhances heme breakdown in kidney, thus impairing heme-dependent cellular functions, such as cytochrome P-450 mediated drug biotransformation. This novel action of the metal results from a potent induction effect on heme oxygenase, the enzyme that catalyzes heme oxidation in microsomes. The possible toxicological implications of this tin effect in the kidney merit further investigation.
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PMID:Tin: a potent inducer of heme oxygenase in kidney. 125 57

Tin is usually present in foods at levels of less than 4 micrograms/g. Higher levels may be found in some processed foods due to the addition of tin-based preservatives and stabilizers or to corrosion and leaching of the metal from unlacquered cans or from tin foils used in packaging. Estimates of dietary intake range from about 0.2 to greater than 5 mg Sn/day. Diets including a high proportion of canned vegetables and fish could supply greater than 30 mg Sn/day. Although intakes from dietary sources are generally considered to be harmless, a variety of adverse effects of tin have been reported, including effects on serum and bone alkaline phosphatase, lactic dehydrogenase, heme oxygenase, and 5-aminolevulinic acid dehydratase. Perturbations in glutathione metabolism have been reported, as have adverse effects on metabolism of essential trace minerals such as copper, zinc, and iron. Specific effects on calcium content of bone, serum, and kidney have also been described. Reported effects vary with the chemical form, dose of tin, and route and frequency of administration. Effects of tin in animal systems and on essential trace mineral absorption and excretion in human volunteers are reviewed. A summary of recent investigations on dietary tin-copper interactions and effects of tin on rat hepatocellular antioxidant protection are also presented.
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PMID:Anti-nutritive effects of dietary tin. 189 7

Tin protoporphyrin (SnPP) and analogs are being studied as possible agents for the prevention of neonatal hyperbilirubinemia through inhibition of heme oxygenase. Because SnPP is a photosensitizer, we studied its role in the photogeneration of carbon monoxide (CO) from organic compounds in vitro. Generation of CO occurred in the presence of 5 microM SnPP and cool white light (19 muW/cm2/nm or 29 W/m2) from SnPP alone, human serum albumin, glucose, histidine, ethanolamine, medium-chain triglycerides, the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH), and human plasma. More detailed studies with human serum albumin and NADPH established that the photogeneration of CO is nearly linear with time and irradiance. It is curvilinear with respect to the SnPP concentration at the concentrations tested, and it is dependent on the presence of O2 in the reactor headspace. Cool white light generated less CO from human serum albumin and NADPH than equidistantly placed blue and green phototherapy light sources. Comparison of SnPP with other metalloporphyrin heme oxygenase inhibitors indicates that tin mesoporphyrin is most and zinc protoporphyrin least photoreactive.
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PMID:In vitro generation of carbon monoxide from organic molecules and synthetic metalloporphyrins mediated by light. 207 72

Pulmonary carbon monoxide (CO) excretion rates (VeCO) were 50% greater, on average, in Bolivian squirrel monkeys (BoSMs) which exhibit a unique fasting hyperbilirubinemia (FH), than in fasted control Brazilian squirrel monkeys (BrSMs). Since the catabolism of heme produces equimolar amounts of CO and bilirubin, the increased VeCOs are consistent with concurrent increases in endogenous bilirubin production rates. Tin-protoporphyrin, a competitive inhibitor of heme oxygenase, significantly decreased both the VeCO and serum bilirubin level in fasted BoSMs. Overproduction of bilirubin may be responsible in part for the marked FH in BoSMs.
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PMID:Increased carbon monoxide excretion in Bolivian squirrel monkeys with fasting hyperbilirubinemia. 221 57

Tin protoporphyrin (SnPP) has been used to suppress hyperbilirubinemia in human neonates through inhibition of heme oxygenase. Some of the subjects exhibited mild erythema upon receiving phototherapy. SnPP and three proposed alternatives, tin mesoporphyrin (SnMP), zinc protoporphyrin (ZnPP) and zinc mesoporphyrin (ZnMP) are potential photosensitizers. We therefore studied the phototoxic effects of these compounds in the neonatal rat model. Fed Wistar rats (24-36 h old) were injected intraperitoneally with up to 40 mumol SnPP/kg body weight, 30 mumol SnMP/kg body weight, 60 mumol ZnPP/kg body weight, or 45 mumol ZnMP/kg body weight. The animals were placed over cool white light (20 microW/cm2/nm) for 12 h. Light exposure resulted in SnPP dose-dependent mortality, and the LD50 was determined to be 11.7 mumol/kg body weight. No deaths were observed in pups treated with up to 20 mumol SnMP/kg; treatment with 30 mumol SnMP/kg resulted in a 40% mortality rate. No fatalities were observed among the light-exposed ZnPP- or ZnMP-treated pups. No deaths were observed among control pups treated with the highest metalloporphyrin doses and kept in the dark; similarly, no mortality was observed in untreated light-exposed control animals. We conclude that (1) SnPP and SnMP are potentially fatal phototoxic substances in the neonatal rat; (2) ZnPP and ZnMP may be safer drugs for neonatal rats receiving light exposure, and (3) further studies are needed to fully assess the photobiological hazards of metalloporphyrin administration to humans.
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PMID:Mortality of metalloporphyrin-treated neonatal rats after light exposure. 236 56

Tin-mesoporphyrin shares many of the properties of its parent compound, tin-protoporphyrin. These include competitive inhibition of heme oxygenase, amelioration of jaundice and suppression of chemically induced hepatic porphyria. Tin-mesoporphyrin is cleared from the plasma of normal subjects with dose-dependent pharmacokinetics (T1/2 = 3.8 hr following i.v. administration of 1 mumole per kg body weight), and small amounts (less than 1% of administered dose) are excreted into the urine and feces. Intramuscular administration of tin-mesoporphyrin resulted, within 2 hr, in plasma concentrations identical to those obtained following i.v. administration, but the compound was not absorbed orally. The only dose-limiting side effect was transient cutaneous photosensitivity. High doses (1 mumole per kg body weight) of tin-mesoporphyrin resulted in significant decreases in plasma bilirubin concentrations at 24 and 48 h after treatment of normal subjects. Administration of both tin-protoporphyrin and tin-mesoporphyrin resulted in decreases in the urinary excretion of heme pathway intermediates in stable hyperexcreters with acute hepatic porphyria.
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PMID:Pharmacokinetics of tin-mesoporphyrin in man and the effects of tin-chelated porphyrins on hyperexcretion of heme pathway precursors in patients with acute inducible porphyria. 271 39

Suppression of hyperbilirubinemia was studied in jaundiced adult and neonatal Gunn rats following treatment with tin-protoporphyrin. The effects of tin-protoporphyrin treatment on heme oxygenase, NADPH cytochrome c reductase, and biliverdin reductase activities were studied in adult jaundiced Gunn rat renal, hepatic and splenic tissues. Hepatic heme oxygenase activity was studied in nonjaundiced and jaundiced Gunn neonates. Significant decreases in plasma bilirubin levels were observed for both adult and neonatal rats treated with 50 or 100 mumol tin-protoporphyrin/kg body weight. Tin-protoporphyrin-treated rats had significantly lower hepatic and renal heme oxygenase activities, splenic and renal cytochrome c reductase activities, and a significantly higher splenic biliverdin reductase activity. Hepatic heme oxygenase activity was also significantly reduced in the neonatal rats.
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PMID:Tin-protoporphyrin suppression of hyperbilirubinemia in the jaundiced Gunn rat. 319 20

Tin(IV)-protoporphyrin (Sn-protoporphyrin) potently inhibits heme degradation to bile pigments in vitro and in vivo, a property that confers upon this synthetic compound the ability to suppress a variety of experimentally induced and naturally occurring forms of jaundice in animals and humans. Utilizing rat liver heme oxygenase purified to homogeneity together with appropriate immunoquantitation techniques, we have demonstrated that Sn-protoporphyrin possesses the additional property of potently inducing the synthesis of heme oxygenase protein in liver cells while, concurrently, completely inhibiting the activity of the newly formed enzyme. Substitution of tin for the central iron atom of heme thus leads to the formation of a synthetic heme analogue that regulates heme oxygenase by a dual mechanism, which involves competitive inhibition of the enzyme for the natural substrate heme and simultaneous enhancement of new enzyme synthesis. Cobaltic(III)-protoporphyrin (Co-protoporphyrin) also inhibits heme oxygenase activity in vitro, but unlike Sn-protoporphyrin it greatly enhances the activity of the enzyme in the whole animal. Co-protoporphyrin also acts as an in vivo inhibitor of heme oxygenase; however, its inducing effect on heme oxygenase synthesis is so pronounced as to prevail in vivo over its inhibitory effect on the enzyme. These studies show that certain synthetic heme analogues possess the ability to simultaneously inhibit as well as induce the enzyme heme oxygenase in liver. The net balance between these two actions, as reflected in the rate of heme oxidation activity in the whole animal, appears to be influenced by the nature of the central metal atom of the synthetic metalloporphyrin.
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PMID:Dual control mechanism for heme oxygenase: tin(IV)-protoporphyrin potently inhibits enzyme activity while markedly increasing content of enzyme protein in liver. 347 Aug 5

Tin(Sn)-protoporphyrin is a potent competitive inhibitor of heme oxygenase and can also suppress naturally occurring or experimentally induced hyperbilirubinemia in animals. In this study we examined the plasma clearance of Sn-protoporphyrin, its persistence in tissues and the time course of heme oxygenase inhibition up to 7 days after administration of doses up to 50 mumol/kg b.w. to adult male rats. After s.c. doses the metalloporphyrin was rapidly and almost completely absorbed. Initial plasma clearance was log-linear with a T 1/2 of approximately 3 h after either i.v. or s.c. administration. Levels of Sn-protoporphyrin in most tissues rose during the first 2 h and persisted for up to 7 days. Concentrations were highest in kidney and liver, were considerably lower in spleen, lung, intestine, adrenal and testes, and as Sn-protoporphyrin concentrations in plasma declined, concentrations in these tissues eventually exceeded simultaneous plasma concentrations. This suggests a varying degree of uptake and binding of the metalloporphyrin in these tissues. There was little or no uptake of Sn-protoporphyrin in heart, brain and red cells. Markedly decreased heme oxygenase activity in liver, kidney and spleen persisted as did Sn-protoporphyrin up to 7 days. The total amount of Sn-protoporphyrin present in tissues and excreta was a fairly constant fraction of the dose (approximately 50%) at time intervals up to 7 days after injection. These results indicate that single doses of Sn-protoporphyrin are rapidly cleared from plasma and persist in tissues and potently inhibit heme oxygenase activity for prolonged periods.
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PMID:Tissue distribution and disposition of tin-protoporphyrin, a potent competitive inhibitor of heme oxygenase. 654 99

Tin-protoporphyrin is a potent competitive inhibitor of heme oxygenase both in vivo in animals and in vitro in isolated enzyme preparations, and when administered to neonatal rats, prevents the development of postnatal hyperbilirubinemia. In this study we examined the effect of the metalloporphyrin on the activity of heme oxygenase in liver, kidney, and spleen, and on the level of bilirubin in plasma in three types of anemic mutant mice with severe hemolytic diseases. We report that the administration of tin-protoporphyrin to anemic mutants homozygous for severe hemolytic disease results in substantial inhibition of heme oxidation in liver, spleen, and kidney and in significant reduction of plasma bilirubin levels. Tin-protoporphyrin thus has the capacity to significantly inhibit in vivo heme degradation and to concurrently diminish plasma bilirubin levels in severe chronic hemolytic disorders.
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PMID:Tin-protoporphyrin suppression of hyperbilirubinemia in mutant mice with severe hemolytic anemia. 668 56


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