Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation.

Abstract

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-protoporhyrin IX chelates (i.e., metal-hemes) studied, Snheme, 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.cheme was the most potent enzyme inhibitor (1I = 0.911 FAM) 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 hyperbilirubinemia that normally occurs postnatally. The effect of the metalloporphyrin in lowering the increased concentrations of serum bilirubin in neonates was prompt (within 1 day) and persisted throughout the 42 days after birth. No deleterious effects of Snheme treatment of the newborn were observed. This demonstrates that a synthetic metalloporphyrin that is a potent competitive inhibitor of heme oxidation can, when administered to the newborn, also prevent the hyperbilirubinemia that normally develops postnatally. The potential clinical implications ofthese findings are evident, and it is suggested that the pharmacological properties of Sn-heme and related synthetic metalloporphyrins merit further study. Chemical blockade of the postnatal induction of heme oxygenase activity [heme,hydrogen-donor In this study we examined the ability of nine metalloporphyrins to alter heme oxygenase synthesis or function in liver, spleen, and other tissues of the rat. Of these compounds three markedly inhibited heme degradation by the enzyme; three substantially enhanced this process,. presumably by inducing heme oxygenase; and three had intermediate effects on the enzyme. Two of these. metal-protoporphyrin IX complexes (Snheme and Mn-heme) were employed in whole animal. studies to determine whether the ability to block heme oxygenase activity demonstrated in vitro could be shown to have physiological expression by also blocking the development of postnatal hyperbilirubinemia in the neonate during the 6-week period after birth.We report here that a metalloporphyrin, Sn-heme, which in vitro acts as a potent competitive substrate for heme in the heme oxygenase reaction can also, when administered to newborn animals, entirely prevent the hyperbilirubinemia that develops in the postnatal period.MATERIALS AND METHODS Materials. Male (160-200 g) and 15-day-pregnant female Sprague-Dawley rats purchased from Holtzman (Madison, WI) were used. To the extent possible pregnancy was synchronized in the latter group of animals so that large numbers of newb...

Antiapoptotic effect of haem oxygenase-1 induced by nitric oxide in experimental solid tumour

“…Analysis for apoptosis and viability of AH136B cells treated with HO inhibitors in vitro AH136B tumour cells, at 5 Â 10 5 cells per well of a six-well polystyrene plate (Falcon, Becton Dickinson Labware, Lincoln Park, NJ, USA), were incubated with various concentrations of the HO inhibitors ZnPP IX and tin protoporphyrin IX (SnPP IX, Frontier Scientific) (Drummond and Kappas, 1981) in Dulbecco's minimum essential medium (Invitrogen Corp., Carlsbad, CA, USA) supplemented with 10% (v v À1 ) fetal bovine serum and 0.5% nonessential amino acids (Invitrogen). After 24 h of culture, the cells were subjected to the cell viability and apoptosis assays of TUNEL staining and caspase-3 activity determination.…”

“…After 24 h of culture, the cells were subjected to the cell viability and apoptosis assays of TUNEL staining and caspase-3 activity determination. Similarly, the cells were treated with CuPP IX, which has no direct inhibitory effect on HO activity in vivo (Drummond and Kappas, 1981) and is a poor HO inhibitor in vitro (Zakhary et al, 1996). Also, the effects of ZnPP IX on cultured cells were examined in the presence of bilirubin (Wako Pure Chemical Co., Ltd, Osaka, Japan) or caspase-3 inhibitor (acetyl-Asp-Met-Gln-Asp-CHO; Peptide Institute, Inc., Osaka, Japan).…”

In Vitro Inhibition of Adult Rat Intestinal Heme Oxygenase by Metalloporphyrins

“…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).…”

Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model

“…Metalloporphyrins (Mps) are synthetic derivatives of heme and also competitive inhibitors of HO (3,7,8). Their potency is based on their central metal and ring-side chains.…”