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Laboratory of Pharmacology

Attallah Kappas

We continue to study the biochemical and pharmacological properties and the clinical uses of synthetic heme analogues as inhibitors of heme oxygenase, the rate-limiting enzyme in heme catabolism to bile pigments. This work has, at the clinical level, culminated in the development of tin mesoporphyrin (SnMP), a potent inhibitor of heme oxygenase, for use in the control of hyperbilirubinemia in newborns. In our most recent studies in term and near-term newborns we have shown that a single, small dose of SnMP administered at an appropriate time after birth is more effective than intensive phototherapy in controlling neonatal hyperbilirubinemia, with the added advantages of simplicity of administration, extremely low cost and of greatly decreased use of medical resources such as extended hospitalization for this problem. SnMP by interdicting bilirubin production shortly after birth eliminates the uncertainties regarding the blood level at which bilirubin may produce CNS toxicity in a given infant and the concerns about treatment thresholds which presently complicate the management of newborn jaundice. SnMP also provides a treatment modality for jaundiced babies born in economic and social settings where no other therapy is available for this disabling and sometimes lethal medical problem.

Characterization of the human heme oxygenase promoter region and identification of the regulatory elements which control heme oxygenase induction is a continuing interest of the laboratory. NK-K β and AP-2 nuclear binding proteins have been shown to play a regulatory role in human heme oxygenase gene expression. We have demonstrated that heme oxygenase participates in a major way in defense mechanisms against agents which induce oxidative damage, such as hemoglobin and free heme, which are released at tissue sites of hemorrhagic and thrombotic injury. In these studies we were able to transfect the human heme oxygenase gene into rabbit coronary endothelial cells, establish selective expression of the human compared with the rabbit gene, and show that overexpression of the human heme oxygenase gene substantially increases endothelial cell resistance to toxicity produced by free hemoglobin and heme. The protective effect of heme oxygenase against heme/hemoglobin toxicity demonstrated in these studies provides direct evidence that the inductive response of this enzyme to agents which produce oxidative injury is an important adaptive mechanism for moderating the severity of cell damage which they produce.