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Treatment of the Porphyrias: Mechanisms of Action

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0022-202X/8 1/ 7701-0 107$02.00/ 0 THE JOU R NA L OF I NVESTIGATI VE D£HMATOL'O(;Y . 77: 107- 11 3.198 1 Vol. 77, No. 1 Copyrighl © 1981 by The Williams & Wilkins Co. Printed in U.S.A. Treatment of the Porphyrias: Mechanisms of Action DAVID R. BICKERS, M.D. Depa.rtm.ent of Derma.tology, Case Western R e"erve University, Cleveland, Ohio, U.S.A. The porphyrias are diseases that result from inherited activity of certain enzymes in t he heme pathway by the admin­ or acquired abnormalities of porphyrin-heme synthesis istration of certain drugs, no permanent alteration can be in the liver and the bone marrow_ Only the hepatic achieved with t he modalities now available. There are, however, porphyrias are known to be aggravated by exposure to a number of t reatments of the various types of porphyria. These a variety of exogenous drugs and chemicals_ Simple range from highly effective modalities such as phlebotomy and avoidance of these agents will reduce the risk of devel­ chloroquine for porphyria cutanea tarda to marginally effective oping hepatic porphyria and may lead to clinical im­ measures such as photoprotection of the skin. Fwthermore, proveme nt in patients with active disease. Some types avoidance of exposure to dJ'ugs and environmental chemicals of therapy of the hepatic porphyrias are effective be­ that can alter heme pathway enzym e activity may be most cause of their ability to modulate the activity of <'l-ami­ helpful in preventing the clinical expression of porphyria. nolevulinic acid synthetase, the rate-limiting enzyme for heme synthesis. Most of the porphyrias are associated PORPHYRIAS AS DISORDERS OF THE REGULATION with cutaneous photosensitivity, the treatment of which OF HEME SYNTHESIS centers about either reducing the excessive production The porphYl'in-heme pathway is ubiquitous in biological sys­ of porphyrins or of inhibiting the photobiological re­ tems. Its activi ty is carefully regulated such that large amounts sponse to these photosensitizing chemicals in the skin. of the end-product heme are formed daily whereas pathway intermediates accumulate and are excreted only in trace amounts. It is currently thought that the bone marrow and the Each of the porphyrias represents the clinical expression of li ver are the major body compartments in which heme synthesis diseases that result from abnormalities in the control of heme occurs. Bone marrow heme is needed for daily erythrocyte syn thesis due to aberrations in the activities of enzymes in t he hemoglobin production and hepatic heme for a variety of heme­ heme pathway. Both inherited and acquired factors play major proteins with relatively rapid tumover. Since heme cannot be roles in the development of these diseases. The clinical mani­ reutilized a nd is broken down into linear tetrapyrroles that festation of the porphyrias appear to be due to the toxic eventuate in bilirubin production, the body must continuously properties of porphyrins and porphyrin precursors. In normal synthesize heme. Heme is required as a prosthetic group by individuals these biochemical intermediates are present only in various apoproteins such as globin and apo-cytoc!11'ome P-450. trace amounts and are therefore virtually innocuous. In patients As cellula]' heme binds to these proteins, heme levels diminish. with porphyria, the presence of excessive amounts of these This decrease in cellular heme leads to enhancement of heme chemicals results in pathologic changes that in tum account for synthesis until "normal" levels are restored. t he recognizable clinical featw-es of these diseases. The rate-limiting step for regulating hepatic heme synthesis Rational therapy of the porphyrias requires detailed knowl­ is the initial enzyme in the pathway, o-aminolevulinic acid edge of porphyrin-heme biosynthesis a nd the genetic and en­ synthetase (ALAS) (Fig 1) [1]. There are everallines of exper­ vironmental factors that influence the activity of this pathway. imental evidence that support the role of mitochondrial ALAS Ideal therapy of the porphyrias would restore a berrant enzyme in controlling the rate of heme synthesis. (1) The activity of activity to normal, thereby reducing the level of the potentially this enzyme is relatively low compared to that of the other toxic porphyrins and porphyrin precw-sors to normal. Unfor­ enzymes in the pathway. (2) The half-life of ALAS is relatively t unately this highly desirable therapeutic endpoint is currently short in mammalian liver (60-180 mins). This is considera bly not attainable. While it does appear possible to influence the less than that of many mitochondrial proteins which have half­ lives of 3-5 days. (3) Activity of the enzyme can be induced or This work was supported by U.S. Public Health1'ervice Grants ES- enhanced by certain types of drugs and other environmental 1900, OH-1l47 and by the Medical Research ServIce of the Veterans Administration. chemicals as well as selected endogenous substances, particu­ Reprint requests to: Dav id R. Bickers, M.D., Professor and Chair­ larly steroid hormones and their metabolites. This "enzyme man, Department of Dermatology, Case Western Reserve University, induction" permits the synthesis of larger amounts of heme Cleveland, Ohio. upon demand particularly for t he production of hepatic cyto­ Abbreviations: chl'Ome P-450, the heme-protein that is an important compo­ AlA: allylisopropylacetamide nent of t he microsomal enzyme system that functions in the ALA: c5 -aminolevulinic acid metabolism of drugs and exogenous chemicals. ALAS: c5-a minolevulinic acid synthetase The hepatocyte appears to be quite sensitive to heme levels: COPRO-O: coproporphyrinogen oxidase as heme falls the strLlctural gene coding for ALAS is dere­ EP: erythropoietic porphyria EPP: erythropoietic proto porphyria pressed. This results in an increased rate of synthesis of this HCP: hereditru'y coproporphyria protein. In response to enhanced ALAS activity cellular heme PBG: porphobilinogen increases. It is utilized for varioLls proteins and also functions PCT: porphyria cutanea tarda as a co-repressor by binding to a putative apo- repressor protein PROTO: protoporphyrinogen which is capable of repressing the synthesis of ALAS (Fig 2). It PROTO-O: protoporphyrinogen ox idase is currently thought that only a relatively small fraction of RBC: red blood ce ll hepatocyte heme (which is not bound to apo-proteins) partici­ TCDD: tetrachlorodibenzo -p-d ioxin pates in this regulatory process (the so-called regulatory heme URO: uroporphyrin or free heme pool) . Certain dJ'ugs which are potent inducers of UROD: uroporphyrinogen decarboxylase UROS: Ul'oporphyrinogen synthetase hepatic ALAS may trigger this effect by competing with heme UROCOS: Ul'oporphyrinoge n cosy nthetase for binding to the aporepressor; fw-thermore, drugs with phar­ VI': vru'iegate porphyria macologic effects that result in reduced cellular heme levels will 107 108 BICKERS Vol. 77, No_ 1 MITOCHONDRION -----------, Thus in the liver the activity of the heme pathway is la.rgely r---------- determined by ALAS which in turn is directly regulated b y , ~ heme levels within the cell. A variety of inherited or acquired fa ctors may influence heme levels and thus interfere with this SUCCINATE GL YCINE ! + I' normally efficient regulatory scheme. Although most experi­ I HOOC-CH2 -CH2 COOH. NH2 CH 2 COOH m ental evidence points to a repression-derepression mecha.nism , . for controlling hepatic ALAS activity, it is also possible that heme could directly inhibit the enzyme. However, the levels I,' 8 - Aminolevulinic acid i required for direct enzyme inhibition (_lO- fiM ) are unlikely to synthetase , occur in vivo. ', (ALAS), The regulation of heme synthesis in the bone marrow is poorly understood but in general ALAS does not appear to be i ! rate-limiting in this tissue. There is experimental evidence to , , indicate that the activity of several enzymes in the h em e ~ HOOC CH CH CCH, NH2 " pathway increases slightly with accelerated demand for bemo­ , 2 2 II , 0 I globin synthesis; furthermore, bone marrow heme pathway enzymes normally function at or near their peak levels and ~ 8 - AMINOLEVULINIC ACID , , (ALA) . cannot be further stimulated by drugs. Recent studies indicate I that in experimental systems, ferrochelatase may become the rate-limiting enzyme for heme synthesis in bone marrow [5]. L~-~-~------~----'l----~-----------_J8- Aminolevulinic acid Since the porphyrias are diseases due either to inherited COOH dehydratase abnormalities in heme pathway enzymes or to the effects of HOOC CH (ALAD) certain drugs and environmental chemicals on these enzymes, I I 2 specific treatment should be capable of correcting these aber­ H 2C CH 2 rations. Furthermore because cutaneous photosensitivity is a major manifestation of th e majority of the porphyrias, nonspe­ 1 PORPHOBILINOGEN cific treatment modalities which have no demonstrable effect upon a bnormal porphyrin-heme synthesis may nonetheless be H C (PSG) 2 beneficial to the patient. H2 N' N The porphyrias are basically of 2 types: hepatic and eryth­ 0H ropoietic. These are listed in Table I. Currently available treat­ FIG 1. o-aminolevulinic ac id synthetase (ALAS) is the rate-limiting ment for each of these will be discussed. enzyme for heme sy nthesis. TREATMENT OF THE PORPHYRIAS Acute Hepatic Porphyrias .9" " 0 REGULATOR OPERATOR STRUCTURAL The acute hepatic porphyrias include acute intermittent por­ \--_.. 8APO ' • • 8mRNA GENE GENE GENE phyria, variegate porphyria and hereditary coproporphyria. These disorders share 2 fundamental characteristics: (1) ele­ c. ~~:~ .., t vated hepatic ALAS and (2) deficient activity of specific en- \. -Feedback Repression Protem Syntt\9SIS _ \ on Ribosomes FEEDBACK INHIBITION aLA r---f--- HEME • s : CYTOCHROME n l tll ''" 8• F."FI"Otlh .,.,... ~ OJ~ejn . P-450 PROTO SUI;CI!YI COA I Proleln • PROTO.O Synlh,Osls PROTOGEN ALA HEME t IoIl1 ochOlld,IOII 1 I CO'R O' O ~ '''' 0,"''", •• • n ALLYLISOPROPYLACETAMIDE " \ 1// / COPROGEN ill +--UROGEN ill +--PBG I URO- D URO- S + ....- URO- COS ---------'» ---- '0 EMf:-_ /I/I}\\ FIG 2.
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  • The Little Imitator-Porphyria: a Neuropsychiatric Disorder

    The Little Imitator-Porphyria: a Neuropsychiatric Disorder

    Journal ofNeurology, Neurosurgery, and Psychiatry 1997;62:319-328 319 REVIEW J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from The little imitator-porphyria: a neuropsychiatric disorder Helen L Crimlisk Abstract Porphyria is derived from the Greek word por- Three common subtypes of porphyria phuros meaning purple. Protoporphyrin IX is give rise to neuropsychiatric disorders; the biologically active substance, an important acute intermittent porphyria, variegate feature of which is its metal binding capacity. porphyria, and coproporphyria. The sec- Both chlorophyll and haem are metallopor- ond two also give rise to cutaneous symp- phyrins and are involved in the processes of toms. Neurological or psychiatric energy capture and utilisation in animals and symptoms occur in most acute attacks, plants. The description of the porphyrins by and may mimc many other disorders. Nobel laureate Hans Fischer' in 1930 as: The diagnosis may be missed because it is "The compounds which make grass green not even considered or because of techni- and blood red." cal problems, such as sample collection indicates the central position of these sub- and storage, and interpretation of results. stances in the biological sciences. A negative screening test does not exclude The porphyrias are a heterogeneous group the diagnosis. Porphyria may be overrep- of overproduction diseases, resulting from resented in psychiatric populations, but genetically determined, partial deficiencies in the lack of control groups makes this haem biosynthetic enzymes. Their manifesta- Department of uncertain. The management of patients tions are broad and their relevance in neu- Neuropsychiatry, with porphyria and psychiatric symptoms ropsychiatric disorders may sometimes be Institute ofNeurology, causes considerable Queen Square, problems.