Nader G. Abraham &
Attallah Kappas talk with ScienceWatch.com about
this month's New Hot Paper in the field of Pharmacology
Article Title: Pharmacological and clinical aspects
of heme oxygenase
Journal: PHARMACOL REV, Volume: 60, Issue: 1, Page: 79-127,
Year: MAR 2008
* New York Med Coll, Dept Med & Pharmacol, Basic Sci
Bldg, Valhalla, NY 10595 USA.
* New York Med Coll, Dept Med & Pharmacol, Valhalla, NY
* Rockefeller Univ Hosp, New York, NY 10021 USA.
The paper collates and brings up-to-date much of the current knowledge
relevant to pharmacology and to clinical medicine concerning the enzyme
heme oxygenase (HO), which catabolizes the breakdown of the oxygen-carrying
respiratory pigment called heme. In this process, heme is converted to the
bile pigment bilirubin; carbon monoxide is generated, and the iron atom,
which is complexed by the porphyrin ring of the molecule, is released.
The background to the discovery of HO is important to appreciate. The
Laboratory of Pharmacology, at The Rockefeller University Hospital, in
which this work was done, was established in 1967 by Professor Attallah
Kappas, who then headed the laboratory and also served subsequently as
Physician-in-Chief of The Rockefeller Hospital and Vice-President of the
The research program of the Kappas group generally focused on problems of
heme biochemistry and pharmacology. The group conducted a broad and
sustained program of research on the hereditary and acquired disorders of
porphyrin-heme synthesis known as the porphyrias—a family of
disorders resulting from deficiencies in the various enzymes of heme
biosynthesis; on the role of specific components of the human diet in
regulating the metabolism of drugs, hormones, and other chemicals by the
heme-containing proteins in the liver known as the cytochromes P450; and
also on genetic and acquired disorders associated with severe
hyperbilirubinemia (jaundice)—especially severe jaundice in newborns.
The problem of how the heme molecule was catabolized into what we can call
its component parts was a subject of great interest to many biochemists
over many years. The problem was apparently solved in the late 1960s by
other investigators whose research led them to the conclusion that the
terminal step in the oxidative degradation of heme—i.e., the cleavage
of the tetrapyrrole ring of heme to form the linear tetrapyrrole
biliverdin, the immediate precursor of bilirubin—was carried out by a
species of cytochrome P-450.
The similarity between the elements of the heme catabolic sequence and
other oxidative systems which had been clearly shown to be dependent on
cytochrome P-450 seemed compelling. It was concluded therefore that the
heme ring was oxidatively ruptured by a form of cytochrome P-450—and
the issue of how heme was degraded to bile pigment seemed resolved.
Nevertheless, there were several features of heme degradation and the
cytochrome P-450-dependent oxidative reactions involving drugs and other
substances which did not entirely match, and this was intriguing as a
biochemical problem. Professor Kappas decided to study this problem further
in order to clarify these dissimilarities and also because of the important
clinical research implications—if it could be shown that HO could be
regulated by some means other than by the action of its natural substrate
heme, a well-known inducer of HO.
The project was undertaken by two members of the laboratory group who,
remarkably, had not previously worked in the porphyrin-heme field and thus
they were presented with an opportunity to enter this new and interesting
field. The end result was that it proved possible to entirely separate the
liver enzyme known as HO from any of the heme-containing cytochromes
P-450—heme is a substrate for HO but not an integral component of the
enzyme, as is the case for cytochrome P-450—and therefore, to begin
its purification, work which finally clarified the mechanism of heme
In addition, the inducibility of the enzyme by non-heme containing
compounds, such as inorganic and organometals was established, thus
permitting studies on the metabolic consequences of the upregulation of HO
activity by chemicals of varied structure. This aspect of HO is now
recognized to have potentially important pharmaceutical significance.
The development of synthetic heme analogues which could competitively
inhibit HO activity followed and thus, the possibility was further offered
of down-regulating, as well as up-regulating the enzyme activity, in
circumstances where one or another action might prove useful.
The examination of the role of the HO system, including the heme catabolism
products CO, biliverdin/bilirubin, and the iron released in the process of
heme degradation, has grown substantially in importance to the discipline
of pharmacology and also in its implications for clinical medicine during
the past three decades.
The HO system has been found to be crucial in cellular defense for numerous
diseases, among which are diabetes, hypertension, heart diseases,
inflammation, transplantation, neurodegenerative and ageing processes, and
the metabolic syndrome. As a result, research has been expanded from a
reexamination of the heme degradation process to the role of the catabolic
products of heme, as well as the metabolic processes which are affected by
perturbations of heme metabolism.
The fact that our paper has been so highly cited indicates the important
role which HO is now recognized to play in diverse metabolic,
physiological, and pathological circumstances. It is already apparent that
the up-or downregulation of HO activity by chemical or genetic means may
have beneficial clinical consequences (e.g., see N.G. Abraham and A.
Kappas: "Heme Oxygenase and the Cardiovascular-Renal System," Free
Radical Biology and Medicine 39: 1-25, 2005) and the increase in the
number of citations in PubMed (17,000 articles in 2007-2008 alone attests
to the importance of the HO system within the research community.
The successful application of HO inhibitors to interdict the development of
severe jaundice in newborns was accomplished by our group—this was
the first application of the principle of regulating HO for clinical
purposes—and provides a clear demonstration that this enzyme
represents a fruitful target for drug development. The successful
development of therapies based on the ability to regulate HO could have
profound implications since the targeted diseases exert a huge cost, both
to the patients, in terms of morbidity and mortality, and to the healthcare
system which is responsible for their care.
Nader G. Abraham, Ph.D.
Professor of Pharmacology
New York Medical College
Valhalla, NY, USA
The Rockefeller University
New York, NY, USA
Attallah Kappas, M.D.
Sherman Fairchild Professor
Head, Laboratory of Pharmacology
and Physician-in-Chief, emeritus
The Rockefeller University
New York, NY, USA
KEYWORDS: SPONTANEOUSLY HYPERTENSIVE-RATS;
HUMAN-ENDOTHELIAL-CELLS; NECROSIS-FACTOR-ALPHA; SMOOTH-MUSCLE-CELLS;
NF-KAPPA-B; GENE PROMOTER POLYMORPHISM; NITRIC-OXIDE SYNTHASE;
BONE-MARROW CULTURE; HEAT-SHOCK-PROTEIN; K-CA CHANNELS.