Selection of metalloporphyrin heme oxygenase inhibitors based on potency and photoreactivity.
The heme oxygenase inhibitor, tin protoporphyrin, is being studied for the prevention of neonatal jaundice. This potential drug, however, is also a photosensitizer that could cause serious and unknown side effects when administered to newborns. Therefore, we have developed in vitro and in vivo procedures for the screening and further characterization of potentially safe heme oxygenase inhibitors. The ideal inhibitor: 1) contains a biocompatible metal, 2) is not degraded in tissues, 3) is a highly potent inhibitor of heme oxygenase, and 4) does not participate in photochemical reactions. Proto- and mesoporphyrin derivatives with the tin, zinc, manganese, chromium, nickel, and magnesium were screened in vitro for suitability. Chromium protoporphyrin and mesoporphyrin were further studied in vitro and in vivo and were found to meet the ideal criteria. Chromium mesoporphyrin appeared to be the most potent in vitro inhibitor of adult Wistar rat tissue heme oxygenase. Four mumol of chromium protoporphyrin or chromium mesoporphyrin/kg body weight, administered intraperitoneally to adult male Wistar rats given a heme load through intraperitoneal administration of 30 mumol heme/kg body weight, caused significant suppression of hemolysis-induced increase in carbon monoxide production to 72 and 44% of control, respectively, 5.5 h after treatment. At t = 6 h, the tissue heme oxygenase activity, measured in vitro, was significantly reduced to 33 and < 5% in liver and to 22 and < 5% in spleen after the administration of chromium protoporphyrin and mesoporphyrin, respectively, but was not reduced in brain. The results show that there exist effective metalloporphyrin heme oxygenase inhibitors without photosensitizing properties.
Vreman
H J
HJ
Department of Pediatrics, Stanford University School of Medicine, California 94305.
Ekstrand
B C
BC
Stevenson
D K
DK
D000818:Animals; D000831:Animals, Newborn; D001663:Bilirubin / Q000378:metabolism / Q000528:radiation effects; D004353:Drug Evaluation, Preclinical; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D017319:Photosensitizing Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D008665:Metalloporphyrins; D017319:Photosensitizing Agents; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin