Immuntoxizitaet von Fremdstoffen bzw. ihren Metaboliten beim Menschen: Untersuchungen zur Aetiopathogenese von Allergien bzw. Autoimmunkrankheiten Schlussbericht

Xenobiotics (e.g. drugs, environmental pollutants) or their reactive metabolites can lead to adverse immune reactions in man, such as allergies or autoimmune diseases. The first part of our project aimed at establishing an in-vitro assay to detect and quantify T-cell reactions against xenobiotics and their metabolites in patients with allergies against drugs. We could show specific sensibilisation of T-cells against a number of drug compounds or metabolites thereof. The aim of the second phase of the project is to demonstrate the influence of the phenotype/geonotype of xenobiotic metabolising enzymes on the susceptibility to adverse immune reactions agains xenobiotics. Ubiquitous xenobiotics are metabolised and detoxified by a set of enzymes. These enzymes are polymorphic, i.e. the actual metabolisation rates and preferred metabolisation paths are genetically determined and differ inbetween individuals. Thus, due to the genetic set-up protein-reactive intermediates could be made preferentially and accumulate upon continuous exposure to a xenobiotic substance. The protein-reactive metabolites can act as 'pro-haptens', and ultimately might cause new self-peptides to be made and presented against which no self-tolerance exists. Using PCR, the genotypes of the most important xenobiotic metabolising enzymes was determined in patients with systemic autoimmune disorders. The results show that polymorphisms of the enzymes N-acetyltransferase, cytochrome P450 1A1, and of chinone reductase are significantly more prevalent in the patients than in the general population. Up to now the DNA of appr. 750 patients has been collected, including full documentation, and can be used for further studies (e.g. the analysis of cytokine polymorphisms). The DNA will be used cooperatively by groups at the University of Duesseldorf and several extramural research institutes (Med. Inst. of Environmental Hygiene, Duesseldorf; Inst. for Occupational-Physiology, Dortmund) to which good contacts have been established. (orig.)SIGLEAvailable from TIB Hannover: DtF QN1(64,59) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Dapsone-induced agranulocytosis. The role of xenobiotic-metabolizing enzymes demonstrated by a case report [Dapson-induzierte agranulozytose. Die rolle fremdstoffmetabolisierender enzyme am beispiel einer kasuistik]

A 34-year-old female patient with a three year history of generalized granuloma annulare was treated systemically with dapsone (DADPS). Six weeks after the onset of treatment, the patient developed an extensive tonsillitis of the base of the tongue with fever and malaise. Routine laboratory work showed a leukocytopenia with agranulocytosis. Further investigation revealed a marked decrease of the enzyme activity of N-acetyltransferase 2, which plays an important role in dapsone metabolism. Treatment included the cessation of dapsone, antibiotic coverage, and G-CSF leading to the rapid improvement of symptoms and normalization of leukocyte counts. Dapsone-induced angina agranulocytotica is a rare event and is interpreted as an idiosyncratic reaction. Depending on genetic polymorphisms of various enzymes, dapsone can be metabolized to immunologically or toxicologically relevant intermediates. Because of the risk of severe hematologic reactions, dapsone should only be employed for solid indications and with appropriate monitoring