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 condition lasting only several days, an effective chemopreventive agent with a relatively short duration of action would be desirable for the treatment of severe neonatal jaundice. To determine the effective duration of action of ZnPP, we administered either 40 nmol/g of body weight ZnPP or 5 microL/g body weight diluent intraperitoneally to neonatal rats 24-36 h after birth. Between 0 and 21 d after ZnPP dosing, the duration of action was investigated through measurements of serum bilirubin and hepatic and splenic HO inhibition, which were correlated to measurements of ZnPP distribution. Significant (p < 0.05) hepatic HO inhibition, 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 nmol/g. Splenic HO was not inhibited measurably by the much lower concentrations of ZnPP found in the spleen (2.8-20.1 nmol/g) between 0 and 21 d after dosing. Furthermore, HO isoform 1 (HO-1) induction was apparently not a confounding factor in the duration of action of ZnPP, because the modest increases in HO-1 protein levels were not sustained longer than 24 h after ZnPP administration. Our findings demonstrated that the duration of action of ZnPP in neonatal rats is less than 1 wk. The reduction in serum bilirubin levels, the short duration of action and minimal confounding effects suggest that ZnPP may be an effective chemopreventive agent for the treatment of severe neonatal jaundice.
Rodgers
P A
PA
Department of Pediatrics, Stanford University School of Medicine, California 94304-0126, USA.
Seidman
D S
DS
Wei
P L
PL
Dennery
P A
PA
Stevenson
D K
DK
D000818:Animals; D000831:Animals, Newborn; D001663:Bilirubin / Q000097:blood*; D001835:Body Weight; D015870:Gene Expression; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D008665:Metalloporphyrins / Q000378:metabolism; D009929:Organ Size; D011524:Protoporphyrins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D008665:Metalloporphyrins; D011524:Protoporphyrins; D012333:RNA, Messenger; C017803:zinc protoporphyrin; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin