The ability of synthetic
metalloporphyrins to suppress
heme oxygenase activity and
bilirubin formation has recently become of considerable clinical and experimental interest for suppression of
jaundice in humans, including
neonatal hyperbilirubinemia. The present investigation compares the biochemical effects of Sn- and Zn-
protoporphyrins on the predominant
heme oxygenase isozyme present in the brain (HO-2) at activity,
protein, and transcript levels and describes the ability of
Sn-protoporphyrin to adversely affect this
isozyme. Specifically, 6 h after a modest dose (50 mumol/kg, i.v.) of
Sn-protoporphyrin,
heme oxygenase activity in rat brain was nearly undetectable. In addition, as revealed by Western blot analysis, HO-2
protein level was decreased by 20% and the electrophoretic behavior of the
protein in the microsomal membranes was altered. Moreover, the activity of
NADPH-cytochrome P-450 reductase, which is required for the oxidation of
heme molecule, was markedly decreased (60% of control). Western immunoblot analysis revealed also a pronounced decrease in the
reductase protein level. The inducible form of
heme oxygenase, HO-1, was not detectable by immunoblotting in brain microsomes of either control or
Sn-protoporphyrin-treated animals. Northern blot analyses did not reveal decreases in the levels of the single HO-1
mRNA (1.8 kb) or the two HO-2 transcripts (1.3 and 1.9 kb), suggesting that
Sn-protoporphyrin mediates its effects on
heme oxygenase isozymes at the
protein level. Zn-
protoporphyrin, on the other hand, had no deleterious effect on brain parameters presently investigated.(ABSTRACT TRUNCATED AT 250 WORDS)