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  • 1. Abu-Bakar, A'edah
    et al.
    Arthur, Dionne Maioha
    Aganovic, Simona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ng, Jack C.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A52011In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 257, no 1, p. 14-22Article in journal (Refereed)
    Abstract [en]

    We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic "BR oxidase''. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301,315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible "BR oxidase" where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced.

  • 2. Abu-Bakar, A'edah
    et al.
    Lämsä, Virpi
    Arpiainen, Satu
    Moore, Michael R.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Hakkola, Jukka
    Regulation of CYP2A5 gene by the transcription factor nuclear factor (erythroid-derived 2)-like 22007In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 35, no 5, p. 787-794Article in journal (Refereed)
    Abstract [en]

    We have previously shown that cadmium, a metal that alters cellular redox status, induces CYP2A5 expression in nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2(-/-)) mice but not in the knockout (Nrf2(-/-)) mice. In the present studies, the potential role of Nrf2 in cadmium-mediated regulation of Cyp2a5 gene was investigated in mouse primary hepatocytes. Cadmium chloride (CdCl2) caused a time-dependent induction of the CYP2A5 at mRNA, protein, and activity levels, with a substantial increase observed within 3 h of exposure. Immunoblotting showed cadmium-dependent nuclear accumulation of Nrf2 within 1 h of exposure. Cotransfection of mouse primary hepatocytes with Cyp2a5 promoter-luciferase reporter plasmids and Nrf2 expression plasmid resulted in a 3-fold activation of Cyp2a5 promoter-mediated transcription relative to the control. Deletion analysis of the promoter localized the Nrf2 responsive region to an area from -2656 to -2339 base pair. Computer-based sequence analysis identified two putative stress response elements (StRE) within the region at positions -2514 to -2505 and -2386 to -2377. Chromatin immunoprecipitation and electrophoretic mobility shift assays showed that interaction of the more proximal StRE with Nrf2 was stimulated by CdCl2. Finally, site-directed mutagenesis of the proximal StRE in Cyp2a5 promoter-luciferase reporter plasmids abolished Nrf2 mediated induction. Collectively, the results indicate that Nrf2 activates Cyp2a5 transcription by directly binding to the StRE in the 5'-flanking region of the gene. This acknowledges Cyp2a5 as the first phase I xenobiotic-metabolizing gene identified under the control of the StRE-Nrf2 pathway with a potential role in adaptive response to cellular stress.

  • 3. Abu-Bakar, A'edah
    et al.
    Moore, Michael R
    Lang, Matti A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5.2005In: Biochem Pharmacol, ISSN 0006-2952, Vol. 70, no 10, p. 1527-35Article in journal (Refereed)
  • 4.
    Abu-Bakar, Aedah
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Satarug, Soisungwan
    NCRET, UQ.
    Marks, Goeffrey
    NCRET, UQ.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Acute cadmium chloride administration induces hepatic and renal CYP2A5 mRNA, protein and activity in the mouse: involvement of transcription factor Nrf22004In: Tox letters, Vol. 148, p. 199-210Article in journal (Refereed)
  • 5. Arpiainen, Satu
    et al.
    Jarvenpaa, Sanna-Mari
    Manninen, Aki
    Viitala, Pirkko
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Pelkonen, Olavi
    Hakkola, Jukka
    Coactivator PGC-1 alpha regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes2008In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 232, no 1, p. 135-141Article in journal (Refereed)
    Abstract [en]

    The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1 alpha expression level by adenovirus mediated gene transfer increased CYP2A5 transcription, Co-transfection of Cyp2a5' promoter constructs with PGC-1 alpha expression vector demonstrated that PGC-1 alpha is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4 alpha response element in the proximal promoter of the Cyp2a5 gene. Chromartin immunoprecipitation assays showed that PGC-1 alpha binds, together with HNF-4 alpha, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1 alpha mediates the expression of Cyp2A5 induced by cAMP in mouise hepatocytes throuch coactivation of transcription factor HNF-4 alpha. This strongly suggests that PGC-1 alpha is the major factor mediating the fasting response of CYP2A5.

  • 6.
    Arpiainen, Satu
    et al.
    Farmakol, Univ Oulu.
    Raffalli-Mathieu, Francoise
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Pelkonen, Olavi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Farmakol, Univ. Oulu.
    Hakkola, Jukka
    Farmakol. Univ Oulu.
    Regulation of the CYP2A5 gene involves an arylhydrocarbon receptor dependent pathway2005In: Molecular Pharmacology, Vol. 67, p. 1325-1333Article in journal (Refereed)
  • 7.
    Camus-Randon, Ann-Marie
    et al.
    Biokemi.
    Raffalli-Mathieu, Francoise
    Uppsala University.
    Bereziat, Jean Claude
    Biokemi.
    MacGregor, Douglas
    Biokemi.
    Konstandi, Maria
    Biokemi.
    Lang, Matti
    Uppsala University.
    Liver injury and expression of cytochromes P450: Evidence that regulation of CYP2A5 is different from that of other major xenobiotic metabolizing CYP enzymes1996In: Toxicol. Appl. Pharmacol., Vol. 138, p. 140-148Article in journal (Refereed)
  • 8.
    Chemin, Isabelle
    et al.
    Biokemi.
    Takahashi, Suneo
    Biokemi.
    Belloc, Claude
    Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Differential Induction of Carcinogen Metabolizing Enzymes in a Transgenic mouse model of Fulminant Hepatitis1996In: Hepatology, Vol. 24, p. 649-656Article in journal (Refereed)
  • 9.
    Christian, Kyle J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Raffalli-Mathieu, Francoise
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Interaction of heterogeneous nuclear ribonucleoprotein C1/C2 with a novel cis-regulatory element within p53 mRNA as a response to cytostatic drug treatment2008In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 73, no 5, p. 1558-1567Article in journal (Refereed)
    Abstract [en]

    We describe a novel cis-element in the 5' coding region of p53 mRNA and its interaction with heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2. This element is located in a putative hairpin loop structure, within the first 101 nucleotides downstream of the start codon. The binding of hnRNPC1/C2 is strongly enhanced in response to the DNA-damaging drug cisplatin [cis-diamminedichloroplatinum(II)] and the cytostatic transcriptional inhibitor actinomycin D (dactinomycin), both known inducers of apoptosis and p53. Strongly stimulated binding is observed in both nuclear and cytoplasmic compartments, and it is accompanied by a cytoplasmic increase of hnRNPC1/C2. Changes in hnRNPC1/C2 protein levels are not proportional to binding activity, suggesting qualitative changes in hnRNPC1/C2 upon activation. Phosphorylation studies reveal contrasting characteristics of the cytoplasmic and nuclear hnRNPC1/C2 interaction with p53 mRNA. Results from chimeric p53-luciferase reporter constructs suggest that hnRNPC1/C2 regulates p53 expression via this binding site. Our results are consistent with a mechanism in which the interaction of hnRNPC1/C2 with a cis-element within the coding region of the p53 transcript regulates the expression of p53 mRNA before and during apoptosis. In addition, we report that preapoptotic signals induced by transcriptional inhibition trigger the appearance of a truncated, exclusively cytoplasmic 43-kDa variant of p53 before apoptosis.

  • 10.
    Christian, Kyle
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Maurel, Patrick
    INSERM, Montpellier.
    Raffalli-Mathieu, Francoise
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Interaction of heterogenous nuclear ribonucleoprotein A1 with cytochrome P450 2A6 mRNA: Implications for posttranscriptional regulation of the CYP2A6 gene2004In: Molecular Pharmacology, Vol. 65, p. 1405-1414Article in journal (Refereed)
  • 11. Daskalopoulos, Evangelos P.
    et al.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marselos, Marios
    Malliou, Foteini
    Konstandi, Maria
    D-2-Dopaminergic Receptor-Linked Pathways: Critical Regulators of CYP3A, CYP2C, and CYP2D2012In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 82, no 4, p. 668-678Article in journal (Refereed)
    Abstract [en]

    Various hormonal and monoaminergic systems play determinant roles in the regulation of several cytochromes P450 (P450s) in the liver. Growth hormone (GH), prolactin, and insulin are involved in P450 regulation, and their release is under dopaminergic control. This study focused on the role of D-2-dopaminergic systems in the regulation of the major drug-metabolizing P450s, i.e., CYP3A, CYP2C, and CYP2D. Blockade of D-2-dopaminergic receptors with either sulpiride (SULP) or 4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl) piperidin-4-ol (L-741,626) markedly down-regulated CYP3A1/2, CYP2C11, and CYP2D1 expression in rat liver. This suppressive effect appeared to be mediated by the insulin/phosphatidylinositol 3-kinase/Akt/FOXO1 signaling pathway. Furthermore, inactivation of the GH/STAT5b signaling pathway appeared to play a role in D-2-dopaminergic receptor-mediated down-regulating effects on these P450s. SULP suppressed plasma GH levels, with subsequently reduced activation of STAT5b, which is the major GH pulse-activated transcription factor and has up-regulating effects on various P450s in hepatic tissue. Levels of prolactin, which exerts down-regulating control on P450s, were increased by SULP, which may contribute to SULP-mediated effects. Finally, it appears that SULP-induced inactivation of the cAMP/protein kinase A/cAMP-response element-binding protein signaling pathway, which is a critical regulator of pregnane X receptor and hepatocyte nuclear factor 1 alpha, and inactivation of the c-Jun N-terminal kinase contribute to SULP-induced down-regulation of the aforementioned P450s. Taken together, the present data provide evidence that drugs acting as D-2-dopaminergic receptor antagonists might interfere with several major signaling pathways involved in the regulation of CYP3A, CYP2C, and CYP2D, which are critical enzymes in drug metabolism, thus affecting the effectiveness of the majority of prescribed drugs and the toxicity and carcinogenic potency of a plethora of toxicants and carcinogens.

  • 12. Daskalopoulos, Evangelos-Panagiotis
    et al.
    Rentesi, Georgia
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marselos, Marios
    Konstandi, Maria
    STRESS-INDUCED MODIFICATION OF THE METABOLIC PROFILE OF THE RAT LIVER2007In: Drug metabolism reviews (Softcover ed.), ISSN 0360-2532, E-ISSN 1097-9883, Vol. 39Article in journal (Other academic)
  • 13.
    Franzen, Anna
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Carlsson, Carina
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Hermansson, Veronica
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    CYP2A5-mediated activation and early ultrastructural changes in the olfactory mucosa: studies on 2,6-dichlorophenyl methylsulfone.2006In: Drug Metab Dispos, ISSN 0090-9556, Vol. 34, no 1, p. 61-8Article in journal (Refereed)
  • 14.
    Franzén, Anna
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Piras, Elena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergström, Ulrika
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Fernandez, E L
    Raffalli-Mathieu, F
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Lang, Matti
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Effects of olfactory toxicants on the expression of CYP2A22003In: Toxicology Letters 144, Suppl 1,, 2003, p. 153-Conference paper (Other scientific)
  • 15.
    Glisovic, Tina
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Ben-David, Yacob
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Cell signalling.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Raffalli-Mathieu, Francoise
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Interplay between hnRNPA1 and cis- acting element in the 3´-UTR of CYP2A5 mRNA is central for high expression of the gene.2003In: Febs letters, Vol. 535, p. 147-152Article in journal (Refereed)
  • 16.
    Glisovic, Tina
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Hobro-Söderberg, Malin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Christian, Kyle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Raffalli-Mathieu, Francoise
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Interplay between transcriptional and posttranscriptional regulation of Cyp2a5 expression.2003In: Biochemical Pharmacology, Vol. 65, p. 1653-1661Article in journal (Refereed)
  • 17. Godoy, W
    et al.
    Albano, RM
    Moraes, EG
    Pinho, PR
    Nunes, RA
    Saito, EH
    Higa, C
    Filho, IM
    Kruel, CD
    Schirmer, CC
    Gurski, R
    Lang, MA
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Pinto, LF
    CYP2A6/2A7 and CYP2E1 expression in human oesophageal mucosa: regional andinter-individual variation in expression and relevance to nitrosaminemetabolism.2002In: Carcinogenesis, Vol. 23, p. 611-Article in journal (Refereed)
  • 18.
    Konstadi, Maria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Farmacol.
    Johnson, Elisabeth
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Oncol.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Stress modulates the enzymatic inducibility by Benzo(a)pyrene in the rat liver2000In: Pharmacol res., Vol. 42, p. 205-211Article in journal (Refereed)
  • 19. Konstandi, Maria
    et al.
    Harkitis, Panagiotis
    Kostakis, Dimitris
    Marselos, Marios
    Johnson, Elizabeth O
    Lang, Matti A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    D-2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E12008In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 82, no 1-2, p. 1-10Article in journal (Refereed)
    Abstract [en]

    This study investigated the role of catecholamine-related signaling pathways in the regulation of hepatic cytochrome P450 (CYP2E1). Central and peripheral catecholamine depletion with reserpine down-regulated CYP2E1. On the other hand, selective peripheral catecholamine depletion with guanethidine increased CYP2E1 apoprotein levels. Enrichment of peripheral catecholamines with adrenaline suppressed p-nitrophenol hydroxylase activity (PNP). PNP activity was also markedly suppressed by L-DOPA. Stimulation of D-2-receptors with bromocriptine up-regulated CYP2E1, as assessed by enzyme activity and protein levels, whereas blockade of D-2-dopaminergic receptors with sulpiride down-regulated this isozyme. These findings indicate that central and peripheral catecholamines have different effects on CYP2E1. Central catecholamines appear related to the up-regulation, whereas the role of peripheral catecholamines is clearly related to the type and location of adrenoceptors involved. D-2-receptor-linked signaling pathways have an up-regulating effect on CYP2E1, while D-1-receptor pathways may down-regulate this isozyme. It is worth noting that the widespread environmental pollutant benzo(alpha)pyrene (13(alpha)P) altered the modulating effect of catecholaminergic systems on CYP2E1 regulation. In particular, whereas stimulation or blockade of adrenoceptors had no effect on constitutive PNP activity, exposure to B(alpha)P modified the impact of central and peripheral catecholamines and alpha(2)-adrenoceptors on CYP2E1 expression. It appears that under the influence of B(alpha)P, alpha(2)-adrenergic receptor-linked signaling pathways increased CYP2E1 apoprotein levels. Given that a wide range of xenobiotics and clinically used drugs are activated by CYP2E1 to toxic metabolites, including the production of reactive oxygen species (ROS), it is possible that therapies challenging dopaminergic receptor- and/or alpha(2)-adrenoceptor-linked signaling pathways may alter the expression of CYP2E1, thus affecting the progress and development of several pathologies.

  • 20.
    Konstandi, Maria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Farmakol..
    Johnson, Elisabeth
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. oncol..
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Noradrenaline, Dopamine,Serotonin; different effects of psychological stress on brain biogenic amines in mice and rats2000In: Pharmacol Res., Vol. 41, p. 341-346Article in journal (Refereed)
  • 21.
    Konstandi, Maria
    et al.
    Farmakol, Univ Ioannina.
    Johnson, Elisabeth
    Farmakol, Univ Ioannina.
    Marselos, Marios
    Farmakol; Univ Ioannina.
    Kostakis, Dimitris
    Farmakol, Univ Ioannina.
    Fotopoulos, A.
    Farmakol, Univ Ioannina.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Stress mediated modulation of B(a)P- induced hepatic CYP1A1: Role of catecholamines2004In: Chem.Biol. Interactions, Vol. 147, p. 65-77Article in journal (Refereed)
  • 22.
    Konstandi, Maria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Farmakol.
    Kostakis, Dimitri
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Farmakol..
    Johnson, Elisabeth
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Onkol..
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Evidence of a2-adrenoceptor involvement in B(a)P induction process of drug metabolizing enzymes:: the effect of stress1998In: Eur.J.Drug Metab. & Pahrmacokin., Vol. 23, p. 491-495Article in journal (Refereed)
  • 23.
    Konstandi, Maria
    et al.
    Farmakol, Univ Ioannina.
    Kostakis, Dimitris
    Farmakol, Univ. Ioannina.
    Harkitis, P.
    Farmakol, Univ. Ioannina.
    Marselos, Marios
    Farmakol. Univ. Ioannina.
    Johnson, Elisabeth
    Farmakol, Univ Ioannina.
    Adamidis, Kyros
    Farmakol. Univ Ioannina.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Role of adrenoceptor-linked signaling pathways in the regulation of CYP1A1 gene expression2005In: Biochem. Pharmacol., Vol. 69, p. 277-287Article in journal (Refereed)
  • 24. Konstandi, Maria
    et al.
    Kostakis, Dimitris
    Harkitis, Panagiotis
    Johnson, Elizabeth O
    Marselos, Marios
    Adamidis, Konstadinos
    Lang, Matti A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Benzo(alpha)pyrene-induced up-regulation of CYP1A2 gene expression: role of adrenoceptor-linked signaling pathways.2006In: Life Sci, ISSN 0024-3205, Vol. 79, no 4, p. 331-41Article in journal (Refereed)
  • 25.
    Konstandi, Maria
    et al.
    Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Effect of Cocaine on Hepatic Drug Metabolism1996In: European Journal of Internal Medicine, Vol. 7, p. 221-226Article in journal (Refereed)
  • 26.
    Konstandi, Maria
    et al.
    Biokemi.
    Lang, Matti
    Uppsala University.
    Effect of Cocaine on Hepatic Drug Metabolism1996In: European Journal of Internal Medicine, Vol. 7, p. 221-226Article in journal (Refereed)
  • 27.
    Konstandi, Maria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Farmakol.
    Marselos, Marios
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Farmakol.
    Camus-Randon, Anne-Marie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Johnson, Elisabeth
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Onkol..
    lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    The role of stress in the regulation of drug metabolizing enzymes in mice.1998In: Eur. J. Drug Metab. & pharmacokinetics, no 23, p. 483-490Article in journal (Refereed)
  • 28. Konstandia, Maria
    et al.
    Segos, Dimitrios
    Galanopoulou, Panagiota
    Theocharis, Stamatios
    Zarros, Apostolos
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marselos, Marios
    Liapi, Charis
    Effects of choline-deprivation on paracetamol- or phenobarbital-induced rat liver metabolic response2009In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 29, no 2, p. 101-109Article in journal (Refereed)
    Abstract [en]

    Choline is an essential nutrient that seems to be involved in a wide variety of metabolic reactions and functions in both humans and rodents. Various pathophysiological states have been linked to choline deprivation (CD). The aim of the present study was to determine the effect of CD upon biochemical, histological and metabolic alterations induced by drugs that affect hepatic functional integrity and various drug metabolizing systems via distinct mechanisms. For this purpose, paracetamol (ACET) or phenobarbital (PB) were administered to male Wistar rats that were fed with standard rodent chow (normally fed, NF) or underwent dietary CD. The administration of ACET increased the serum aspartate aminotransferase levels in NF rats, while CD restricted this increase. On the other hand, ACET suppressed alkaline phosphatase levels only in CD rats. Moreover, CID prevented the PB-induced increase of the mitotic activity of hepatocytes. The administration of ACET down-regulated CYP1A2 and CYP2B1 expression in CD rats, while up-regulating them in NF rats. The administration of PB suppressed CYP1A2 apoprotein levels in CD rats, whereas the drug had no effect on NF rats. The PB-induced up-regulation of CYP2B, CYP2E1 and CYP1A1 isozymes was markedly higher in CD than in NF rats. In addition, PB increased glutathlone-S-transferase activity only in CD rats. Hepatic glutathione content (GSH) was suppressed by ACET in NF rats, whereas the drug increased GSH in CD rats. Our data suggest that CD has a significant impact on the hepatic metabolic functions, and in particular on those related to drug metabolism. Thus, CD may modify drug effectiveness and toxicity, as well as drug-drug interactions, particularly those related to ACET and PB.

  • 29. Kotsovolou, Olga
    et al.
    Ingelman-Sundberg, Magnus
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marselos, Marios
    Overstreet, David H.
    Papadopoulou-Daifoti, Zoi
    Johanson, Inger
    Fotopoulos, Andrew
    Konstandi, Maria
    Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression2010In: Progress in Neuro-psychopharmacology and Biological Psychiatry, ISSN 0278-5846, E-ISSN 1878-4216, Vol. 34, no 6, p. 1075-1084Article, review/survey (Refereed)
    Abstract [en]

    The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7ethoxyresorufin-O-dealkylase (EROD) and 16 alpha-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(alpha)pyrene (B(alpha)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(a)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity.

  • 30.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    CYP2A5/CYP2A6 in search for function1995In: Eur. J. Drug metabolism and pharmacokinetics, Vol. special issue, p. 29-30Article in journal (Refereed)
  • 31.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    CYP2A5/CYP2A6 in search for function1995In: European Journal of drug metabolism and Pharmacokinetics, Vol. special issue, p. 29-30Article in journal (Refereed)
  • 32.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cytochrome P450 and PAH metabolism:: In " Int. programme on chemical safety"; UN Env. programme, WHO1997In: UN Env. programme no 8, Vol. 8Article, review/survey (Other (popular scientific, debate etc.))
  • 33.
    Lang, Matti
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Pelkonen, Olavi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Farmakol..
    Metabolism of xenobiotics and chemical carcinogenesis1999Book (Refereed)
  • 34.
    Lang, Matti
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Raffalli-Mathieu, Francoise
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Cytochrome P450 RNA-protein interactions2002Book (Refereed)
  • 35.
    Lindell, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Karlsson, MO
    Department of Pharmaceutical Biosciences.
    Lennernas, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Pahlman, L
    Faculty of Medicine, Department of Surgical Sciences.
    Lang, MA
    Department of Pharmaceutical Biosciences.
    Variable expression of CYP and Pgp genes in the human small intestine.2003In: Eur J Clin Invest, Vol. 33, p. 493-Article in journal (Refereed)
  • 36.
    Lindell, Monica
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Variable exepression of CYP and Pgp genes in human small intestine2003In: Eur. J. Clinical Investigation, Vol. 33, p. 493-499Article in journal (Refereed)
  • 37.
    Lindell, Monica
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lennernäs, Hans
    Department of Pharmacy.
    Expression of genes encoding for drug metabolising cytochrome P450 enzymes and P-glycoprotein in the rat small intestine: comparison to the liver2003In: Eur. J. Drug Metab. & Pharmacokin., Vol. 28, p. 41-48Article in journal (Refereed)
  • 38.
    MacGregor, Douglas
    et al.
    Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Carbon tetrachloride; Genetic effects and other modes of action1996In: Mutation Res., Vol. 366, p. 181-195Article in journal (Refereed)
  • 39.
    Malats et al, Nuria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Mol tox.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lung cancer in nonsmokers and GSTM1 and GSTT1 genetic polymorphism2000In: Cancer Epid. Biomarkers & Prev., Vol. 9, p. 827-835Article in journal (Refereed)
  • 40.
    Oscarson, Michael
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Tox..
    McLellan, Ron
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Gullsten, Harriet
    Farmakol.
    Yue, Q-Y
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Characterization and PCR based detection of a CYP2A6 gene deletion found at a high frequency in in a Chinese population1999In: Febs lett., Vol. 448, p. 105-110Article in journal (Refereed)
  • 41.
    Pelkonen, Olavi
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Farmakol.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Xenobiotic metabolizing enzymes and cancer risk.: correspondance between genotype and phenotype1999Book (Refereed)
  • 42.
    Pelkonen, Olavi
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Raunio, Hannu
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Rautio, Arja
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Pasanen, Markku
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    The metabolism of coumarins: In; Coumarins: Biology, Applications and mode of action.1997Book (Refereed)
  • 43.
    Pelkonen, Päivi
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Interaction of AflatoxinB1 with CYP2A5 and its mutants:: Correlation with Metabolic activation and toxicity1997In: Chem. Res. in Toxicology, Vol. 10, p. 85-90Article in journal (Refereed)
  • 44. Pinto, LF
    et al.
    Moraes, E
    Albano, RM
    Silva, MC
    Godoy, W
    Glisovic, T
    Lang, MA
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rat oesophageal cytochrome P450 (CYP) monooxygenase system: comparison tothe liver and relevance in N-nitrosodiethylamine carcinogenesis.2001In: Carcinogenesis, Vol. 22, p. 1877-Article in journal (Refereed)
  • 45.
    Piras, Elena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Franzén, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fernández, Estíbaliz L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Raffalli-Mathieu, Françoise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lang, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cell-specific expression of CYP2A5 in the mouse respiratory tract: effects of olfactory toxicants.2003In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 51, no 11, p. 1545-1555Article in journal (Refereed)
    Abstract [en]

    We performed a detailed analysis of mouse cytochrome P450 2A5 (CYP2A5) expression by in situ hybridization (ISH) and immunohistochemistry (IHC) in the respiratory tissues of mice. The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells. In the respiratory and transitional epithelium there was no or only weak expression. The nasolacrimal duct and the excretory ducts of nasal and salivary glands displayed expression, whereas no expression occurred in the acini. There was decreasing expression along the epithelial linings of the trachea and lower respiratory tract, whereas no expression occurred in the alveoli. The hepatic CYP2A5 inducers pyrazole and phenobarbital neither changed the CYP2A5 expression pattern nor damaged the olfactory mucosa. In contrast, the olfactory toxicants dichlobenil and methimazole induced characteristic changes. The damaged Bowman's glands displayed no expression, whereas the damaged epithelium expressed the enzyme. The CYP2A5 expression pattern is in accordance with previously reported localization of protein and DNA adducts and the toxicity of some CYP2A5 substrates. This suggests that CYP2A5 is an important determinant for the susceptibility of the nasal and respiratory epithelia to protoxicants and procarcinogens.

  • 46.
    Raffalli-Mathieu, Francoise
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Geneste, Olivier
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Characterization of two nuclear proteins interacting with CYP1A2 mRNA: regulation of binding and possible role in the expression of Cyp1A2 gene.1997In: Eur. J. Biochem., Vol. 245, p. 17-24Article in journal (Refereed)
  • 47.
    Raffalli-Mathieu, Francoise
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Glisovic, Tina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Ben David, Yacob
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Cell signalling.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Heterogenous Nuclear Ribonucleoprotein A1 and regulation of the Xenobiotic -Inducible gene CYP2A52002In: Molecular Pharmacology, Vol. 61, p. 795-799Article in journal (Refereed)
  • 48.
    Satarug, Soi
    et al.
    Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Induction of Cytochrome P450 2A6 expression in humans by the carcinogenic parasite infection, opisthorchiasis viverrini.1996In: Cancer Epid., Biomarkers & Prevention, Vol. 5, p. 795-800Article in journal (Refereed)
  • 49.
    Söderberg, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Raffalli-Mathieu, Françoise
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Identification of a regulatory cis-element within the 3 '-untranslated region of the murine inducible nitric oxide synthase (NOS) mRNA: interaction with heterogeneous nuclear ribonucleoproteins I and L and role in the NOS gene expression2007In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 44, no 4, p. 434-442Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the role of heterogeneous nuclear ribonucleoprotein I (hnRNPI) and hnRNPL in the regulation of the murine inducible nitric,oxide synthase (iNOS) gene during inflammation. Treatment of mice with lipopolysaccharide (LPS)/D-galactosamine, or of RAW 264.7 cells with LPS/interferon-gamma (IFN-gamma), strongly increased iNOS expression while reducing hnRNPI levels and complex formation between hnRNPI/hnRNPL and the 3'-untranslated region (3'-UTR) of iNOS mRNA. Introduction of the iNOS 3'-UTR to a luciferase reporter gene reduced its expression in RAW 264.7 cells. However, when hnRNPI and hnRNPL binding sites were deleted, luciferase expression was recovered. LPS/IFN-gamma increased the luciferase activity of the full-length 3'-UTR construct compared to control, while its effects on the deletion constructs were modest. The results indicate that LPS/IFN-gamma induce iNOS through a mechanism involving hnRNPI and hnRNPL binding to iNOS 3'-UTR. Our data suggest that iNOS mRNA degradation is promoted upon binding of hnRNPI and hnRNPL to a destabilizing region within its 3'-UTR, while inflammatory stimuli causing dissociation of the mRNA-protein complex, yield a more stable transcript. This appears to be particularly significant during extended inflammatory stimuli, resulting in sustained nitric oxide production. The critical event launching this process appears to be the degradation of hnRNPI.

  • 50.
    Söderberg, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Raffalli-Mathieu, Françoise
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Regulation of the murine inducible nitric oxide synthase gene by dexamethasone involves a heterogeneous nuclear ribonucleoprotein I (hnRNPI) dependent pathway2007In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 44, no 12, p. 3204-3210Article in journal (Refereed)
    Abstract [en]

    Glucocorticoids down regulate the inducible nitric oxide synthase (iNOS) gene both transcriptionally and post-transcriptionally. The posttranscriptional events are suggested to involve destabilization of the iNOS transcript although the molecular mechanisms for this effect are not known. Recently, our laboratory demonstrated a lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-induction-dependent interaction of heterogeneous nuclear ribonucleoprotein (hnRNP) I and hnRNPL with a destabilizing element contained in the Tuntranslated region (UTR) of iNOS mRNA. The aim of this study was to investigate if dexamethasone, which down regulates iNOS, is able to modulate this protein-mRNA interaction. As expected, dexamethasone inhibited the induction of iNOS by LPS and IFN-gamma in RAW 264.7 cells, and destabilized the iNOS mRNA. Dexamethasone also counteracted the LPS/IFN gamma-induced disappearance of a gel shifted iNOS mRNA-protein complex containing hnRNPI and hnRNPL. UV cross-linking and Western blot analyses revealed that the RNA-binding and levels of hnRNPI, which decreased by LPS/IFN gamma treatment, were restored by dexamethasone. The results support our hypothesis that hnRNPI is pivotal in the post-transcriptional regulation of iNOS and strongly suggest that hnRNPI is one of the trans-acting factors mediating the post-transcriptional effects of dexamethasone.

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