The liver excretes large amounts of heme into bile when heme oxygenase is inhibited competitively by Sn-protoporphyrin. Academic Article uri icon

Overview

abstract

  • 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 same experimental model, Sn-protoporphyrin substantially decreased the conversion of heme, derived from heat-damaged erythrocytes, to biliary bilirubin. This decrease in biliary bilirubin output was accounted for entirely by a prompt and marked increase in biliary excretion of unmetabolized heme. The enhanced biliary excretion of unmetabolized heme following administration of Sn-protoporphyrin is a newly defined and biologically important response associated with use of this synthetic heme analogue. The features of the action of this compound in vivo--suppression of formation of the potentially neurotoxic metabolite, bilirubin; enhancement of disposal of the untransformed substrate (heme) of the enzyme that it inhibits; and its own elimination without metabolic alteration--define some of the characteristics of a therapeutically useful chemical.

publication date

  • February 1, 1985

Research

keywords

  • Bile
  • Heme
  • Heme Oxygenase (Decyclizing)
  • Liver
  • Metalloporphyrins
  • Mixed Function Oxygenases
  • Porphyrins
  • Protoporphyrins

Identity

PubMed Central ID

  • PMC397154

Scopus Document Identifier

  • 0343877380

Digital Object Identifier (DOI)

  • 10.1073/pnas.82.3.896

PubMed ID

  • 3856238

Additional Document Info

volume

  • 82

issue

  • 3