Expression of rat liver heme oxygenase gene during development

We studied the genetic expression during fetal development of heme oxygenase, the rate-limiting enzyme in the oxidation of heme to bilirubin. The transcription of the heme oxygenase gene in livers of fetal and neonatal rats (9 days before birth to 28 days after birth) was examined. Hybridization analyses of total RNA from livers of these animals using cDNA for rat heme oxygenase as the probe revealed a single mRNA species of approximately 18 S in every sample examined. The mRNA level was above the adult level throughout the course of study and reached a maximum 24 h after birth. The high level of heme oxygenase mRNA in fetuses was unaffected when Sn-protoporphyrin, a potent inhibitor of heme oxygenase, was administered to their mothers. On the other hand, the mRNA levels in the mothers treated with this heme analog were substantially increased, possibly by the same mechanism as for the induction by heme. Sn-protoporphyrin potentiates induction of heme oxygenase mRNA in cobalt chloride-pretreated rats, and also acts as a potent inhibitor of heme oxygenase enzyme activities. Our results also indicate that high heme oxygenase levels during fetal maturation are due to an increase in transcription of the gene. Thus, Sn-protoporphyrin which crosses the placenta controls fetal hyperbilirubinemia by direct enzyme inhibition.