Dioxins and other polycyclic aromatic compounds formed during the combustion of waste and fossil fuels represent a risk to human health, as well as to the well being of our environment. The primary sequence and structure of AhR 3 in different species have been highly conserved during the course of evolution, suggesting that this receptor, which belongs to the family of basic helix-loop-helix nuclear transcription factors, plays an important physiological role(s) in homeostatic processes (1, 2). However, despite intensive studies, this physiological role and the endogenous activators of the AhR remain to be elucidated (3). At the cellular level, activated AhR interacts with various signal transduction pathways; induces biotransformation enzymes; alters the cell cycle, cell adhesion, and migration; and causes apoptosis or aberrant cell growth (4 -7). In vivo, the AhR plays significant roles in connection with development, immunological and reproductive functions, and adaptive responses to light and xenobiotics (8 -11). Compounds of this nature exert carcinogenic and endocrinedisrupting effects in experimental animals by binding to the orphan aryl hydrocarbon receptor (AhR). Understanding the mechanism of action of these pollutants, as well as the physiological role(s) of the AhR, requires identification of the endogenous ligand(s) of this receptor. We reported earlier that activation of AhR by ultraviolet radiation is mediated by the chromophoric amino acid tryptophan (Trp), and we suggested that a new class of compounds derived fromThe AhR protein has been shown to bind the compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as well as similar highly lipophilic halogenated and non-halogenated hydrocarbons leading to cardiovascular, carcinogenic, and endocrine effects (12-16). Consequently, most studies designed to explore the functions of this receptor have been performed with TCDD. One remarkable feature of activation of AhR by dioxinlike compounds is sustained induction of both cytochromes P450 and other metabolizing enzymes, whereas other agonists cause only transient induction of these enzymes. It seems likely that for purposes of regulation, endogenous ligands of AhR are metabolized rapidly, so that the use of persistent xenobiotics such as dioxins to investigate this receptor might be inappropriate. A striking discrepancy between the effects of different types of AhR activators was made evident in two recent studies (17,18). The authors showed that FICZ, the suggested physiologic AhR ligand, boosted T H 17-cell differentiation and worsened the experimentally induced autoimmune encephalomyelitis, whereas TCDD increased levels of T reg and suppressed the pathological effects in myelin-immunized mice.* This work was supported by Swedish Research Council (Formas), the Swedish Radiation Safety Authority, Karolinska Institutet, and the Sven and Lily Lawskis Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertiseme...

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Soluble SULTs (sulfotransferases) are important in the regulation of messenger molecules and the elimination of xenobiotics. However, sulfo-conjugation of various substrates can also lead to the formation of reactive metabolites that may induce cancer and cause other damage. The aim of the present study was to identify the SULT forms expressed in the human gastrointestinal tract, especially the colon and rectum (common sites for cancer), and to determine their cellular localization. Normal colonic or rectal tissue, resected with tumours, was obtained from 39 subjects. For comparison, we additionally studied one to four samples from stomach, jejunum, ileum, cecum and liver. SULTs were detected by immunoblotting, immunohistochemistry and measurement of enzyme activities. SULT1A1, 1A3 and 1B1 were found in all parts of the gastrointestinal tract, often exceeding levels in liver (where these forms were present at high, undetectable and low levels respectively). They were predominantly localized in differentiated enterocytes. SULT1E1 and 2A1 were only detected in liver, jejunum, ileum and cecum. SULT1C1 was readily found in stomach, but was negligible elsewhere. SULT1A2 was present at low levels in individual samples. The remaining forms were not detected with the limitation that only high levels could be recognized with the antisera used. In conclusion, SULTs are abundant in the gastrointestinal tract of man. We suspect that they are involved in the presystemic elimination of bioactive food-borne components, including aglycones released by gut microbiota, as well as the bioactivation of some procarcinogens.