Prevention of Neonatal Hyperbilirubinemia in Rhesus Monkeys by Tin-protoporphyrin

Cornelius, Charles E.; Rodgers, Pamela A.

doi:10.1203/00006450-198408000-00010

Cited by 62 publications

(34 citation statements)

References 8 publications

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“…As shown in several in vivo studies (4)(5)(6)(7)(8), the administration of SnPP to j/j neonates causes rapid decreases in hepatic heme oxygenase activity and serum bilirubin. However, the reduction of serum bilirubin occurred within 60 min after SnPP administration, whereas the decrease in hepatic heme oxygenase activity continued for 2 h with a trend similar to that reported by Anderson et al (20).…”

Section: Resultsmentioning

confidence: 99%

“…rates developing hyperbilirubinemia in newborn rats (4,5) and rhesus monkeys (6) and reduces the plasma bilirubin level in adult mutant mice with hemolytic anemia (7,8). j/j Gunn rats with an inherited deficiency of hepatic bi1irubin:uridine diphosphate-glucuronyltransferase activity (9) are hyperbilirubinemic throughout life (10) and develop bilirubin-induced cerebellar hypoplasia (1 1-14).…”

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confidence: 99%

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Pharmacological and Biological Effects of Tin-Protoporphyrin on Neonatal Hyperbilirubinemic Gunn Rats

et al. 1988

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ABSTRACT. Our study was undertaken to examine the pharmacological and biological effects of tin-protoporphyrin, a competitive inhibitor of heme oxygenase, on 5-or 6-day-old homozygous Cjlj) Gunn rats with hereditary unconjugated hyperbilirubinemia. When j / j neonates were injected subcutaneously with 20 pmol of tin-protoporphyrintkg of body weight, hepatic heme oxygenase activity decreased to 30% of the initial level 2 h after administration and remained low during the next 46 h. However, the reduction of serum bilirubin was more rapid and transient, reaching the minimum value (40% of the initial level) at 1 h and increasing thereafter at a rate almost comparable to that in nontreated j/j rats. The mortality rate of j / j rats was strikingly reduced by the administration of 1 to 100 pmol of tin-protoporphyrin/kg; the most effective dose was 5 pmol/kg (8% compared with 80% in non-treated j/j rats). However, the protective effect of tin-protoporphyrin on bilirubin cerebellopathy (cerebellar hypoplasia) was less marked than expected. Possible implications of our results are discussed. (Pediatr Res 24: 209-912, 1988)

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Pharmacological and Biological Effects of Tin-Protoporphyrin on Neonatal Hyperbilirubinemic Gunn Rats

et al. 1988

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“…l), have been shown to be effective in lowering serum bilirubin levels in a wide range of animal species (2)(3)(4)(5)(6)(7)(8), by competitively inhibiting heme oxygenase activity (7)(8)(9)(10). Additionally, SnMP and ZnMP have recently been found to be equally effective at about 10-fold lower doses (1 1, 12).…”

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In Vitro Inhibition of Adult Rat Intestinal Heme Oxygenase by Metalloporphyrins

1989

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ABSTRACT. We determined the inhibitory effects of concentrations of tin-and zinc protoporphyrin (1-100 pM) and mesoporphyrin (0.1-10 pM) on the in vitro heme oxygenase (HO) (E.C.1.14.99.3) activity in liver, spleen, and intestine 13, 000 % g tissue supernatants from fasted adult male Wistar rats through measurement of carbon monoxide by gas chromatography. All four metalloporphyrins inhibited intestinal HO, under the light-limited conditions of these experiments. The zinc porphyrins showed a clear concentration dependency over the entire range, reducing activity to near zero levels at their highest concentrations. The tin porphyrins reduced HO activity to 26% of initial levels, but the inhibition was not clearly concentration dependent. Liver and spleen supernatants exhibited concentration dependent inhibition by all four metalloporphyrins. We also assessed the effect of light on HO activity measurements. HO determinations in the light (8 pW/cmz/nm) yielded higher HO activity than for reactions performed in the dark. The presence of light and SnPP appeared to stimulate the H O activity of intestinal preparations thus overcoming the observed inhibition. Light and SnPP also decreased to a lesser degree the inhibition for the spleen preparation, but not for the liver. We conclude that heme oxygenase activity measurements via CO determination need to be conducted in the absence of light, in particular when photosensitizers are present. Furthermore, it appears that intestinal HO behaves in a quantitatively different way from other tissues, under varying conditions of metalloporphyrin inhibition and light exposure. (Pediatr Res 26:362-365,1989) Abbreviations HO, heme oxygenase ZnPP, zinc protoporphyrin ZnMP, zinc mesoporphyrin SnPP, tin protoporphyrin SnMP, tin mesoporphyrin Jaundice, a problem common to the human neonate, results from increased bilirubin production and immaturity of the bilirubin-conjugating mechanism in the liver. HO, the rate-limiting enzyme (E.C. 1.14.99.3) in the heme catabolic pathway, cleaves

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“…This rate-limiting enzyme in the heme catabolic pathway (4) catalyzes the equimolar formation of bilirubin and CO. In vivo studies with TP have demonstrated the drug's effectiveness in lowering serum bilirubin levels in rats ( 3 , in mice with severe hemolytic anemia (6) in rhesus monkeys (7), and in man (8). Preliminary studies in our laboratory suggested that a single dose of TP has no suppressive effect on the excretion rate of CO (VeCO) in suckling rats (9, 10) unless the animals are first treated with broad spectrum antibiotics (1 I).…”

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Lack of Inhibition of Intestinal Heme Oxygenase by Antibiotics and Tin-Protoporphyrin

et al. 1988

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A B S T R A a . W e assessed the in vivo and in vitro effects of antibiotics and tin-protoporphyrin (TP) on intestinal heme oxygenase (HO) activity using a gas chromatographic assay. This method measures the carbon monoxide produced from heme in the presence of NADPH. After in vivo administration of kanamycin (10 mg/kg body weight), ampicillin (200 mg/kg body weight) or neomycin (60 mg/ kg body weight) with or without T P (65 pmol/kg body weight) to suckling rats, no significant difference in HO activity along the small intestine was observed. I n vitro exposure of adult rat intestinal preparations to the antibiotics showed no significant decrease in H O activity between control and experimental tissue preparations. A concentration-dependent stimulatory effect of neomycin was observed. Subcutaneous administration of T P (25 pmol/kg body weight) to adult male Wistar rats revealed no significant inhibition of the intestine. However, in vitro addition of T P (12.5 pM) to the control tissue preparations of adult Wistar rats revealed highly significant inhibition in liver and spleen when compared to the unexposed control tissues. In contrast, when T P was added to control intestinal preparations no inhibition was observed. These findings suggest that suckling rat intestinal heme oxygenase is not inhibited by in vivo treatment with high concentrations of kanamycin, ampicillin, or neomycin. Furthermore, these antibiotics are not in vitro inhibitors of adult rat intestinal HO. Finally, adult rat intestinal H O is not inhibited either in vivo or in vitro by a concentration of TP that significantly inhibits liver and spleen activity. (Pediatr Res 23: 50-53, 1988) Abbreviations CO, carbon monoxide TP, tin-protoporphyrin HO, heme oxygenase VeCO, excretion rate of C O TP, a synthetic heme analog, has been reported to be a competitive inhibitor of HO (1-3). This rate-limiting enzyme in the heme catabolic pathway (4) catalyzes the equimolar formation of bilirubin and CO. In vivo studies with TP have demonstrated the drug's effectiveness in lowering serum bilirubin levels in rats ( 3 , in mice with severe hemolytic anemia (6) in rhesus monkeys (7), and in man (8). Preliminary studies in our laboratory suggested that a single dose of TP has no suppressive effect on the excretion rate of CO (VeCO) in suckling rats (9, 10) unless

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Prevention of Neonatal Hyperbilirubinemia in Rhesus Monkeys by Tin-protoporphyrin

Cited by 62 publications

References 8 publications

Pharmacological and Biological Effects of Tin-Protoporphyrin on Neonatal Hyperbilirubinemic Gunn Rats

Pharmacological and Biological Effects of Tin-Protoporphyrin on Neonatal Hyperbilirubinemic Gunn Rats

In Vitro Inhibition of Adult Rat Intestinal Heme Oxygenase by Metalloporphyrins

Lack of Inhibition of Intestinal Heme Oxygenase by Antibiotics and Tin-Protoporphyrin

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