The regulation of
heme oxygenase activity in the developing neonate is essential to the control of
bilirubin production as well as intracellular
heme and hemoprotein metabolism. The coordinated activity of the microsomal
enzymes,
heme oxygenase and
NADPH-
cytochrome c (P450)
reductase, and the cytosolic
enzyme biliverdin reductase is responsible for the degradation of
heme. The complete reaction sequence requires
oxygen and
NADPH, and produces
bilirubin and
carbon monoxide in equimolar amounts. Although
heme oxygenase expresses a rather broad range of substrate affinities, the oxidative degradation of
heme is exclusively alpha-specific.
Heme oxygenase is found in several tissues, with significant activity levels in the liver, spleen, and erythropoeitic tissue.
Heme oxygenase activity is inducible by
heme and other
metalloporphyrins,
hormones,
starvation, stress, toxins, and
xenobiotics.
Heme oxygenase induction is generally considered to be the result of an increased
protein synthesis and gene transcription. This hypothesis is supported by recent studies of the
heme oxygenase gene that identified inducer
element binding sites responsive to
metal administration, heat shock, and nutrient availability. In the developing fetus and neonate, hepatic
heme oxygenase activity and
mRNA levels are elevated above that of the adult. This suggests that the elevated
heme catabolism observed in neonates may be associated with an increased transcription of the
heme oxygenase gene. The apparent induction of hepatic
heme oxygenase during the neonatal period is probably the result of tissue-specific and time-dependent transcriptional regulating factors including potentially
hormones and
heme. Several
metalloporphyrins, such as the
tin and
zinc porphyrin complexes, inhibit
heme oxygenase activity and thus have therapeutic potential for the treatment of
neonatal jaundice. Recent studies suggest that the meso- and bis-glycol derivatives of these
metalloporphyrins may be more potent inhibitors of
heme oxygenase activity in vitro and in vivo than the
protoporphyrin structures. As structural analogues of
heme, however, these compounds may also have other less desirable effects on the regulation of
heme and hemoprotein metabolism, particularly in the developing neonate.