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.