Preface

BATLLE, ALCIRA; ROSSETTI, MARIA VICTORIA

Porphyrias and associated pathologies. Biochemistry and Molecular Biology, Cellular and Molecular Biology Special Issue, Vol 55, Part I

CMB edition

Lugar: Noisy Le Grand; Año: 2009; p. 1 - 5

To start with, we wish to thank Professor Dr. Raymond Wegmann “The Founding President” and Professor Dr. Jean-Michel Maixent, “The President”, Editors-in-Chief of Cellular and Molecular BiologyTM for their generous invitation to become Guest- Editor and Co-Guest Editor of this special theme issue on “Porphyrias and associated pathologies. Biochemistry and Molecular Biology”, which will be published in two Volumes, Part I, appearing now, February 16 th, 2009 and the next, Part II, scheduled for June 2009. Although Cellular and Molecular BiologyTM has already published three others special issues on this subject, one in 1997, and two in January and December 2002, …”to have another issue on “Porphyrins and Porphyrias” is not too much, since it belongs to one of the modern problems for which orphan drugs are requested”… (quoted from Professor Dr. Raymond Wegmann, Cellular and Molecular BiologyTM, , 2002, 48, 823). We also wish to thank Mr Mourad Fares, Executive Editor of CMB, for his support, composition and editing of the papers. The articles put together in Part I of this theme issue, come from the highest experts in the world in this field, biologists, physicians, chemists, physics, all of them leading porphyrinologists, which will assure, will make Part I as well as the coming Part II, a highly important reference issue for the future. Therefore we are also deeply thankful to all the authors for their contributions and most important their collaboration in making possible the production of this theme CMB issue. “Porphyrins and Porphyrias”, since the middle of the 50’s, porphyrinologists from all over the world have been meeting at least once or later more than once, mostly in Europe and USA, to discuss about the latest innovative results on the biochemistry, molecular biology, regulation and functional mechanisms of the enzymes involved at each step of the porphyrins biosynthesis, which have been isolated, cloned and even chrystalized, and its related diseases: the Porphyrias. In 1997, Professor Robert Aquaron, attempted to list a number of the International Porphyrins and Porphyrias Meeting, mostly hold in Europe, since 1955, until then. However the Gordon Research Conferences, started in 1968, occurring in USA, every two years ( about 15) were just mentioned as well as the Tetrapyrrole Discussion Group Meetings, gathering somewhere in Europe, more often in UK, every nine months since 1967 (by then they were about 20 meetings). Porphyrins and Porphyrias, certainly, one of the most important and endless theme for discussion. Some of us have had the honour and pleasure of having been associated, known and being personally involved in Porphyrins and Porphyrias research for nearly 50 years by now, also having had the pionners in this field as our mentors, something to celebrate, so we will, after reading this special issue of CMB. Porphyrins synthesis is one of the most fundamental attributes of all living cells. Central to the fundamental processes of photosynthesis and respiration, are chlorophylls and haem, respectively, which are porphyrins, that is the reason why, Lemberg and Ledge in 1949, coined the expression “porphyrins are the pigments of life”, could it be anything more important than that?. We would wish to partially quote one of us (Batlle, CMB TM, 2002, 48, 823), when saying that porphyrins are unique and intriguing molecules, historically having a geologic and a biologic medical chapter. The former going back many millions of years, when the formation of porphyrinlike compounds and porphyrins was contemporary with the development of life on earth. The latter started at the beginning of nineteen century when iron-free hematin was obtained by Scherer in 1941, after treating dried blood with concentrated sulphuric acid. This pigment was later purified by Thudichum in 1867, who named it “cruentine” and described for the first time its “splendid bloodred” fluorescence. The term “porphyrin” was soon after coined by Hoppe Seyler in 1871.” As already stated, porphyrin biosynthesis is one of the most fundamental attributes of all living cells. Classical isotope tracer studies from the laboratories of Shemin, Rimington, Granick and Neuberger, identified the precursors and intermediates in the haem biosynthetic pathway marking the beginning of a whole new field of research in the biogenesis of these pigments. Then, most of the eight enzymatic steps involved were identified. Today all the enzymes have been cloned and sequenced and most of them have also been crystallized. The porphyrin pathway is very finelly controlled. In most tissues and species, Aminolevulic Acid Synthetase (ALA-S) is the regulatory enzyme. Regulation occurs by feedback inhibition of ALA-S, so haem deficiency, owing to blocking the pathway at some step, as it happens in the Porphyrias, releases this inhibition. The term “porphyria”, gradually emerged after Stokvis(1889) reporting the death of an elderly women, excreting dark red urine after having received sulfonal. Human porphyrias are specific inherited or acquired defects, each representing a partial failure of one of the seven enzymes beyond ALA-S and they are characterised by a typical excretion pattern of porphyrin intermediates. We would like to recall that porphyrins are the only photosensitizers synthesized in the cells and the best examples of these endogenous sensitizers are the porphyrin intermediates formed and accumulated in the cutaneous porphyrias, producing the characteristic skin photosensitization. Photodynamic Therapy (PDT) is a promising new modality of cancer treatment, which involves the combination of, a photosensitizing agent, which is taken up selectively and retained by tumoural cells, and light of an appropriate wavelength. Separately, each of these factors is harmless by itself, though, when combined, in the presence of oxygen, cytotoxic reactive oxygen species are produced, leading to irreversible cellular damage, causing cell death and tumour destruction. After either exogeneous administration or endogenous synthesis, porphyrins finally accumulate in higher proliferative cells. Light energy absorbed by the photosensitizer (PS) can produce fluorescence. The tumour localizing properties of the PS have been extensively employed for the Photodetection (PD) and diagnosis, as well as for the PDT of tumours. In humans, mutations in the Protoporphyrinogen oxidase (PPO) gene, the enzyme catalizing the penultimate reaction in heme synthesis, resulted in decreased PPO activity leading to Variegate Porphyria (VP), a dominantly inherited disorder characterized by photosensitive skin lesions and a propensity to develop neurovisceral crisis. In the paper “Peroxidase activity of cytochrome c facilitates the Protoporphyrinogen oxidase reaction”, Mark Shepherd and Harry Dailey, have very elegantly demonstrated that given the cellular location of PPO and the abundance of Cyt.c in the intermembrane space of mitochondria, generation of free radicals, through the peroxidase activity of Cyt c, might potentially impact on heme synthesis in vivo, particularly in conditions of low oxygen or hypoxia. In Hereditary Coproporphyria (HCP), another mixed Porphyria, mutations in the gene of Coproporphyrinogen Oxidase (CPO), lead to reduced CPG activity. Clinical symptoms are rare before puberty and are mostly neurological and less commonly cutaneous. Caterina Aurizi and coworkers, in their paper “Four Novel Mutations of the Coproporphyrinogen III Oxidase Gene”, have characterized 4 novel mutations and one already described in 5 Italian unrelated families. The clinical manifestation of porphyrias are often associated with exposure to precipitating agents, including polyhalogenated aromatic hydrocarbons, alcohol abuse, stress, estrogens ingestion, iron overload and infection with Hepatitis C virus (HCV), less frequently, Hepatitis B virus (HBV) infection with the Human Immunodeficiency virus (HIV). It is also known that in some porphyrias, mild to moderate hepatic iron overload plays a key role in its pathogenesis. Hemochromatosis is the commonest cause of primary iron overload and some mutations in the hemochromatosis gene (HFE), associated with hereditary Hemochromatosis, have been found to be more frequent in PCT. Association of porphyrias with other pathologies, such as diabetes, lupus, leukaemia, Hansen’s disease and cancer has been reported. There is also association of porphyrias with the treatments used for other pathologies, such as estrogen-therapy in prostate cancer and hemodialysis in patients with renal failure. Porphyrias are often multifactorial, therefore, knowledge of all risk or etiological factors in each patient is most important for the management of the disease. In the paper “Awareness is the name of the game: Clinical and Biochemical Evaluation of a Case of a Girl Diagnosed with Acute Intermittent Porphyria Associated with Autism”, A.S. Luder, R. Mamet, I. Farbstein and N. Shoenfeld, reported for the first time, the association of an AIP patient diagnosed at the age of 15 years, with late autism, first presented at the age of 4 years. Most unusual was that her urinary ALA and PBG were normal, even during the crisis, not compatible with symptomatic AIP, which was only established on the basis of a 64% reduction of RBC PBG Deaminase, later confirmed with the finding of a known AIP mutation. It is strongly recommended that porphyria should be considered in children with late autism, mainly in relation to atypical or unexpected reactions to medication. The association in three patients with AIP and end-stage renal disease (ESRD) has been reported in the paper “Porphyrin precursors and porphyrins in three patients with Acute Intermittent Porphyrias and ends-stage renal disease under different therapy regimens” by E. Sardh, D.H.E. Andersson, A. Henrichson and P. Harper. The authors have followed the course of three patients with recurrent attacks of AIP and end-stage renal disease (ESRD). Plasma PBG and porphyrins were considerably increased in the three patients. In a previous study, the mean urinary and plasma PBG/ALA ratio in biochemically active AIP patients with conserved renal function was 2.0 (normal 0.3) and plasma porphyrin levels were normal (< 10 nmol/L). In this study they show that the progression to ESRD was paralleled by an increase in urinary and plasma PBG/ALA ratio to reach levels above 6 and higher. Plasma porphyrin increased to levels above 1000 nmol/L leading to cutaneous lesions resembling PCT The development of kidney failure was a devastating complication in these AIP patients with chronic active disease, leading to unavoidable deterioration of peripheral veins, progression of peripheral neuropathy, dialysis treatment and secondary cutaneous lesions. The clinical course could not be reversed by medical treatment in any of the cases. The combined liver and kidney transplantation is now beeing considered as a final therapeutic option. Porphyrias are pharmaco and toxicogenetic diseases and the N-methyl-diethyl-aspartate (NMDA) receptor has been reported to play a key role in several acute and chronic neuropathologic syndromes. ALA accumulates in acute porphyrias due to a deficiency in the heme biosynthetic pathway. Considering that glutamate uptake inhibition caused by ALA could by one of the reasons conducing to porphyric neuropathy, it was of interest to evaluate the effect of porphyrinogenic agents on NMDA glutamatergic system. . In the paper “Glutamatergic system: another target for the action of porphyrinogenic agents”, by J. Lavandera, M. Fossatiu, J. Azcurra, A. Batlle and A.M. Buzaleh, the authors have shown that the