Abstract
Sn(tin)-protoporphyrin, a potent competitive inhibitor of heme oxygenase, can suppress hyperbilirubinemia in animal neonates and significantly reduce plasma bilirubin levels in animals and man. To further explore the biological actions and metabolic disposition of Sn-protoporphyrin, we have examined its effect in the suckling neonate when administered to the mother either 24-48 h before or immediately after birth. Sn-protoporphyrin, when administered before birth, crossed the placental membranes, inhibited fetal heme oxygenase, and suppressed the transient hyperbilirubinemia that occurs in the neonate after birth in a dose-dependent manner. Tissue heme oxygenase activity in the neonate was also lowered in a dose-dependent manner. The blood-brain barrier of the neonate was permeable to Sn-protoporphyrin for a period of between 20-28 d of postnatal life. Sn-protoporphyrin, however, was not retained in brain, but left the brain space with a t1/2 of 1.7 d. In addition, Sn-protoporphyrin administered once at birth to neonates inhibited brain heme oxygenase in a dose-dependent manner. The results of this study demonstrate that Sn-protoporphyrin can cross the placental membranes, inhibit tissue heme oxygenase activity in the fetus, and can also, following such prenatal treatment, suppress the hyperbilirubinemia of the newborn animal.
Full text
PDF





Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Anderson K. E., Simionatto C. S., Drummond G. S., Kappas A. Tissue distribution and disposition of tin-protoporphyrin, a potent competitive inhibitor of heme oxygenase. J Pharmacol Exp Ther. 1984 Feb;228(2):327–333. [PubMed] [Google Scholar]
- Cornelius C. E., Rodgers P. A., Bruss M. L., Ahlfors C. E. Characterization of Gilbert-like syndrome in squirrel monkeys (Saimiri sciureus). J Med Primatol. 1985;14(2):59–74. [PubMed] [Google Scholar]
- Cornelius C. E., Rodgers P. A. Prevention of neonatal hyperbilirubinemia in rhesus monkeys by tin-protoporphyrin. Pediatr Res. 1984 Aug;18(8):728–730. doi: 10.1203/00006450-198408000-00010. [DOI] [PubMed] [Google Scholar]
- Drummond G. S., Kappas A. An experimental model of postnatal jaundice in the suckling rat. Suppression of induced hyperbilirubinemia by Sn-protoporphyrin. J Clin Invest. 1984 Jul;74(1):142–149. doi: 10.1172/JCI111394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Drummond G. S., Kappas A. Chemoprevention of neonatal jaundice: potency of tin-protoporphyrin in an animal model. Science. 1982 Sep 24;217(4566):1250–1252. doi: 10.1126/science.6896768. [DOI] [PubMed] [Google Scholar]
- Drummond G. S., Kappas A. Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6466–6470. doi: 10.1073/pnas.78.10.6466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Drummond G. S., Kappas A. Suppression of hyperbilirubinemia in the rat neonate by chromium-protoporphyrin. Interactions of metalloporphyrins with microsomal heme oxygenase of human spleen. J Exp Med. 1982 Dec 1;156(6):1878–1883. doi: 10.1084/jem.156.6.1878. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Halac E., Jr, Sicignano C. Re-evaluation of the influence of sex, age pregnancy, and phenobarbital on the activity of UDP-glucuronyl transferase in rat liver. J Lab Clin Med. 1969 Apr;73(4):677–685. [PubMed] [Google Scholar]
- Kappas A., Drummond G. S. Control of heme metabolism with synthetic metalloporphyrins. J Clin Invest. 1986 Feb;77(2):335–339. doi: 10.1172/JCI112309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kappas A., Drummond G. S., Simionatto C. S., Anderson K. E. Control of heme oxygenase and plasma levels of bilirubin by a synthetic heme analogue, tin-protoporphyrin. Hepatology. 1984 Mar-Apr;4(2):336–341. doi: 10.1002/hep.1840040227. [DOI] [PubMed] [Google Scholar]
- Kappas A., Simionatto C. S., Drummond G. S., Sassa S., Anderson K. E. The liver excretes large amounts of heme into bile when heme oxygenase is inhibited competitively by Sn-protoporphyrin. Proc Natl Acad Sci U S A. 1985 Feb;82(3):896–900. doi: 10.1073/pnas.82.3.896. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
- Maines M. D., Kappas A. Study of the developmental pattern of heme catabolism in liver and the effects of cobalt on cytochrome P-450 and the rate of heme oxidation during the neonatal period. J Exp Med. 1975 Jun 1;141(6):1400–1410. doi: 10.1084/jem.141.6.1400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maines M. D. Regional distribution of the enzymes of haem biosynthesis and the inhibition of 5-aminolaevulinate synthase by manganese in the rat brain. Biochem J. 1980 Aug 15;190(2):315–321. doi: 10.1042/bj1900315. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Milleville G. S., Levitt M. D., Engel R. R. Tin protoporphyrin inhibits carbon monoxide production in adult mice. Pediatr Res. 1985 Jan;19(1):94–96. doi: 10.1203/00006450-198501000-00025. [DOI] [PubMed] [Google Scholar]
- Pentschew A., Garro F. Lead encephalo-myelopathy of the suckling rat and its implications on the porphyrinopathic nervous diseases. With special reference to the permeability disorders of the nervous system's capillaries. Acta Neuropathol. 1966 Jun 1;6(3):266–278. doi: 10.1007/BF00687857. [DOI] [PubMed] [Google Scholar]
- Roth M. Dosage fluorimétrique de la bilirubine. Clin Chim Acta. 1967 Sep;17(3):487–492. doi: 10.1016/0009-8981(67)90225-2. [DOI] [PubMed] [Google Scholar]
- Sassa S., Drummond G. S., Bernstein S. E., Kappas A. Long-term administration of massive doses of Sn-protoporphyrin in anemic mutant mice (sphha/sphha). J Exp Med. 1985 Sep 1;162(3):864–876. doi: 10.1084/jem.162.3.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sassa S., Drummond G. S., Bernstein S. E., Kappas A. Tin-protoporphyrin suppression of hyperbilirubinemia in mutant mice with severe hemolytic anemia. Blood. 1983 May;61(5):1011–1013. [PubMed] [Google Scholar]
- Simionatto C. S., Anderson K. E., Drummond G. S., Kappas A. Studies on the mechanism of Sn-protoporphyrin suppression of hyperbilirubinemia. Inhibition of heme oxidation and bilirubin production. J Clin Invest. 1985 Feb;75(2):513–521. doi: 10.1172/JCI111727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simionatto C. S., Anderson K. E., Sassa S., Drummond G. S., Kappas A. Fluorometric measurement of tin-protoporphyrin in biological samples. Anal Biochem. 1984 Aug 15;141(1):213–219. doi: 10.1016/0003-2697(84)90448-2. [DOI] [PubMed] [Google Scholar]
- Tenhunen R., Marver H. S., Schmid R. Microsomal heme oxygenase. Characterization of the enzyme. J Biol Chem. 1969 Dec 10;244(23):6388–6394. [PubMed] [Google Scholar]
- Thaler M. M., Gemes D. L., Bakken A. F. Enzymatic conversion of heme to bilirubin in normal and starved fetuses and newborn rats. Pediatr Res. 1972 Mar;6(3):197–201. doi: 10.1203/00006450-197203000-00008. [DOI] [PubMed] [Google Scholar]
- Yoshinaga T., Sassa S., Kappas A. Purification and properties of bovine spleen heme oxygenase. Amino acid composition and sites of action of inhibitors of heme oxidation. J Biol Chem. 1982 Jul 10;257(13):7778–7785. [PubMed] [Google Scholar]