DURATION OF ACTION AND TISSUE DISTRIBUTION OF ZINC PROTOPORPHYRIN IN NEONATAL RATS

Zinc protoporphyrin IX (ZnPP) has been shown to inhibit heme oxygenase (HO) activity effectively in vivo and has potential in the treatment of neonatal jaundice. Because this is a transitional or temporary cond ition lasting only several days, an effective chemopreventive agent wi th a relatively short duration of action would be desirable for the tr eatment of severe neonatal jaundice. To determine the effective durati on of action of ZnPP, we administered either 40 nmol/g of body weight ZnPP or 5 mu L/g body weight diluent intraperitoneally to neonatal rat s 24-36 h afterbirth. Between 0 and 21 d after ZnPP dosing, the durati on of action was investigated through measurements of serum bilirubin and hepatic and splenic HO inhibition,which were correlated to measure ments of ZnPP distribution. Significant (p < 0.05) hepatic HO inhibiti on, ranging from 27 to 51%, was observed in the liver between 1 and 4 d after dosing, concurrent with a 23-28% reduction in serum bilirubin levels, and was associated with ZnPP tissue concentrations of 27-38 nm ol/g. Splenic HO was not inhibited measurably by the much lower concen trations of ZnPP found in the spleen (2.8-20.1 nmol/g) between 0 and 2 1 d after dosing. Furthermore, HO isoform 1 (HO-1) induction was appar ently not a confounding factor in the duration of action of ZnPP, beca use the modest increases in HO-1 protein levels were not sustained lon ger than 24 h after ZnPP administration. Our findings demonstrated tha t the duration of action of ZnPP in neonatal rats is less than 1 wk. T he reduction in serum bilirubin levels, the short duration of action a nd minimal confounding effects suggest that ZnPP may be an effective c hemopreventive agent for the treatment of severe neonatal jaundice.