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Prevention of Neonatal Hyperbilirubinemia by Tin

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Prevention of Neonatal Hyperbilirubinemia by Tin Proc. NatL Acad. Sci.-USA Vol. 78, No. 10, pp. 6466-6470, October 1981 Medical Sciences Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation [neonatal jaundice/heme oxidase (decyclizing)/metalloporphyrins] GEORGE S. DRUMMOND AND ATTALLAH KAPPAS The Rockefeller University Hospital, New. York, New York 10021 Communicated by Edward H. Ahrens, Jr., June 23, 1981 ABSTRACT The effects of various metalloporphyrins on he- markedly inhibited heme degradation by the enzyme; three patic heme oxygenase (EC 1. 14.99.3) activity were examined in substantially enhanced this process,. presumably by inducing order to identify compounds that could inhibit heme degradation heme oxygenase; and three had intermediate effects on the en- to bile pigment and might therefore be utilized to suppress the zyme. Two of these. metal-protoporphyrin IX complexes (Sn- development of hyperbilirubinemia in the newborn. Among nine heme and Mn-heme) were employed in whole animal. studies metal-protoporhyrin IX chelates (i.e., metal-hemes) studied, Sn- to determine whether the ability to block heme oxygenase ac- heme, Mn-heme, and Zn-heme substantially diminished heme physiolog- oxygenase activity in vivo in the rat. These metalloporphyrins act tivity demonstrated in vitro could be shown to have as competitive inhibitory.substrates in the heme oxygenase reac- ical expression by also blocking the development of postnatal tion but are not themselves oxidatively. degraded. Sn.cheme was hyperbilirubinemia in the neonate during the 6-week period the most potent enzyme inhibitor (1I = 0.911 FAM) in liver, spleen, after birth. kidney, and.skin. Sn-heme administered to newborn animals We report here that a metalloporphyrin, Sn-heme, which in within the first 72 hr after birth blocked the postnatal increase in vitro acts as apotent competitive substrate forheme in the heme heme oxygenase activity that occurs in various tissues. Its effect oxygenase reaction can also, when administered to newborn on the enzyme levels was prompt and protracted. Sn-heme admin- animals, entirely prevent the hyperbilirubinemia that develops istration also entirely prevented the development of hyperbili- in the postnatal period. rubinemia that normally occurs postnatally. The effect of the me- talloporphyrin in lowering the increased concentrations of serum MATERIALS AND METHODS bilirubin in neonates was prompt (within 1 day) and persisted Materials. Male (160-200 g) and 15-day-pregnant female throughout the 42 days after birth. No deleterious effects of Sn- Sprague-Dawley rats purchased from Holtzman (Madison, WI) heme treatment of the newborn were observed. This demon- were used. To the extent possible pregnancy was synchronized strates that a synthetic metalloporphyrin that is a potent compet- in the latter group ofanimals so that large numbers ofnewborn itive inhibitor of heme oxidation can, when administered to the could be studied within the same postnatal time period; the newborn, also prevent the hyperbilirubinemia that normally de- study involved a total of 750 neonates divided approximately velops postnatally. The potential clinical implications ofthese find- equally among the control.and experimental groups described ings are evident, and it is suggested that the pharmacological prop- below. Metalloporphyrins were .purchased from Porphyrin erties of Sn-heme and related synthetic metalloporphyrins merit Products (Logan, UT) and all other chemicals were ofthe high- further study. est grade obtainable from either Fisher or Sigma. Chemical blockade of the postnatal induction of heme oxygen- TreatmentofAnimals and Preparation ofMicrosomes. Male ase activity [heme,hydrogen-donor:oxygen oxidoreductase (a- rats were injected at subcutaneous sites with the protopor- methene-oxidizing, hydroxylating), EC 1.14.99.3] and suppres- phyrin IX chelates of manganese (Mn2+), tin (Sn'"), nickel sion of the hyperbilirubinemia that results from fetal erythro- (Ni2+), zinc (Zn2+),. magnesium (Mg2+),. copper (Cu2+), cad- cyte lysis and exaggerated heme oxidation during this period mium (Cd2+), cobalt (Co3+), or iron (Fe2+) at various doses up has not been demonstrated in the whole animal. Total blockade to 125 tumol/kg body weight in order to determine the ability of heme oxygenase induction by certain transition and related ofthese various heme complexes to induce or inhibit the activity elements can, however, be achieved by concurrent adminis- ofmicrosomal heme oxygenase in liver. The metalloporphyrins tration of other metal ions (1, 2). Moreover, certain synthetic were taken up in a small volume of 0.2 M NaOH adjusted to metalloporphyrins, as we earlier demonstrated (3), can act as pH 7.4 with 1 M HC1 and made up to final volume with 0.9% competitive substrates for heme in the. heme oxygenase reac- NaCl. Control animals were injected with an equivalent volume tion, though they do not themselves undergo oxidative degra- of saline. The animals were given access to water but were dation by the enzyme. These findings indicate that heme ox- starved for 16 hr after metalloporphyrin administration; prior ygenase activity can be regulated at the catalytic level as well to decapitation. Microsomes were prepared as described (1). as at the synthetic level. Appropriate competitive inhibition of Neonates received subcutaneous injections of either Sn- heme oxidation by the-enzyme might therefore be expected to heme or Mn-heme (100 Amol/kg body weight) prepared as de- suppress or prevent the hyperbilirubinemia that occurs in the scribed above but in a final volume of 0.1 ml. The regimen of neonatal period. administration was a single injection of the synthetic hemes at In this study we examined the ability of nine metallopor- birth, and 12, 24, 48, and 72 hr later. The dose of metallopor- phyrins to alter heme oxygenase synthesis or function in liver, phyrin employed was selected to fall within the range examined spleen, and other tissues of the rat. Ofthese compounds three in the in vivo studies in the adult male animal (see above). The time period during which each compound was administered The publication costs ofthis article were defrayed in part by page charge conforms with that in which, postnatally, heme oxygenase ac- payment. This article must therefore be hereby marked "advertise- tivity is known to be rapidly increasing (4). Control neonates ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. received an equivalent volume of saline at each of these time 6466 Medical Sciences: Drummond and Kappas Proc. Natd Acad. Sci. USA 78 (1981) 6467 points. Groups ofneonates (6-30 animals per group) were then Competitive Inhibition ofHeme Oxygenase Activity in Vitro sacrificed at the times indicated in the figures and assays were by Metalloporphyrins. The apparent Km for heme in the splenic performed for serum bilirubin and tissue enzymes as described (Fig. 1) and hepatic heme oxygenase systems was determined below. to be 12.5 ,uM, which is within the range reported previously Enzyme Assays. Heme oxygenase was assayed as described for microsomal preparations (3, 9). The addition of Sn-heme (5), and bilirubin formation was calculated on the basis of an (0.1 ,uM) to splenic heme oxygenase incubation mixtures re- extinction coefficient of 40 mM-'cm-' and the difference of sulted in a marked competitive inhibition of enzyme activity, absorbance between 464 nm and 530 nm. The assay was carried with a >10-fold increase [12.5 ,uM to 136 uM (Fig. 1)] in the out on the microsomal fractions isolated from liver, kidney, and Km for heme. In separate experiments with both spleen and spleen and on the 9000 X g fraction from skin. s-Aminolevu- liver heme oxygenase preparations, the 14 (inhibitor constant) linate synthase was measured as described (6). All assays were for Sn-heme was determined to be 0.011 ZM. Zn-heme pro- performed on an Aminco Chance DW2A spectrophotometer in duced an increase in the apparent Km for heme to 71 .M (spleen the split beam mode. microsomes) and its 14 was determined to be 0.212 ,uM. Mn- Total bilirubin was estimated in serum fluorimetrically by the heme, as previously noted (10), interfered somewhat with the method, ofRoth (7); the variation in replicate samples of serum spectrophotometric determination of the product of the heme was <5% (7). Protein concentration was determined with crys- oxygenase assay; Mn-heme, however, appeared to be a potent talline bovine albumin as standard (8). The data were analyzed inhibitor ofboth spleen and liver heme oxygenase activity, with by the standard t test and the value of P < 0.05 was regarded a 14 that was intermediate between the 1Ys ofSn-heme and Zn- as denoting significance. heme. On the basis ofthese findings (Table 1, Fig. 1) Sn-heme and RESULTS Mn-heme were selected for in vivo studies in neonatal rats to Effect of Various Metal-Protoporphyrin IX Complexes on determine ifthey were capable ofblocking the development of Heme Oxygenase and 8-Aminolevulinate Synthase Activities hyperbilirubinemia in the postnatal period. Treatment began in Liver. Metalloporphyrins, administered at adose of50 Amol/ immediately after birth, as indicated in Materials and Methods, kg body weight, were examined in adult male rats for their ef- and the study continued throughout the subsequent 6-week fects in vivo on the activities of heme oxygenase and 6-amino- period. levulinate synthase, the rate-limiting enzymes of heme catab- Effects ofSn-Heme and Mn-Heme Administration on Heme olism and synthesis, respectively (Table 1). Hepatic heme Oxygenase Activity in the Neonate. The effects ofSn-heme and oxygenase activity, measured 16 hr after metalloporphyrin Mn-heme administration on hepatic heme oxygenase levels in administration, was lowered (50-60%) by Sn-heme, Mn-heme, neonates during, the 6-week study period are shown in Fig. 2. and Zn-heme, increased (100-400%) by Cd-heme, Fe-heme, Hepatic heme oxygenase activity rose rapidly after birth as ex- and Co-heme, and largely unaffected by the other compounds pected (4), reaching levels 4-fold above those characteristic of examined.
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