INSULIN AS A REGULATOR OF FLAVIN-CONTAINING MONOOXYGENASE ENZYME IN STREPTOZOTOCIN-INDUCED DIABETIC RATS
The flavin-containig monooxygenase enzyme (FMO) family is one of the major microsomal monooxygenase enzyme systems involved in drug metabolism. Its physiological role in mammals, aside from the transformation of trimethylamine into trimethylamine N-oxide, is unknown. FMO1 and FMO3 isoforms are predominant in the liver of experimental animals and humans, respectively. The activity of FMO changes in certain pathophysiological conditions, for example in diabetes. Our main goal was to study whether insulin has a role in FMO regulation. For this purpose we induced experimetal diabetes in rats using streptozotocin, and then the diabetic rats received insulin supplementation. Changes in FMO function were determined at the level of enzymatic activity and gene expression. FMO activity was measured using an FMO specific substrate, benzydamine. The FMO1 and FMO3 gene expressions were observed by q-RT-PCR. Along that, the changes in abundance and activities of hepatic cytochrome enzyme system were characterized in order to support and complete the results in our experimental model system. It was shown that both, FMO activity and FMO1 mRNA level increased approximately 2-fold in diabetic rats. These levels were restored to the control level upon insulin supplementation and no change was observed upon insulin treatment of non-diabetic animals. A repressor function was proposed for insulin, because FMO activity was induced in insulin-deficiency, restored on insulin supplementation to control level and had no influence per se. As a high correlation was found between the FMO activity and the blood glucose level of diabetic rats, blood glucose level was suggested to be a good marker for elevated FMO activity.
Furthermore, we have recognized that FMO1 and FMO3 isoforms showed distinct sensitivity to insulin-deficiency.
1. Dalmadi B, Leibinger J, Szeberényi Sz, Borbás T, Farkas S, Szombathelyi Zs and Tihanyi K (2003) Identification of metabolic pathways involved in the biotransformation of tolperisone by human microsomal enzymes. Drug Metab Dispos, 31: 631-636.
2. Szökő É, Tábi T, Borbás T, Dalmadi B, Tihanyi K and Magyar K. (2004) Assessment of the N-oxidation of deprenyl, methamphetamine and amphetamine enantiomers by chiral capillary electrophoresis; an in vitro metabolism study.
Electrophoresis, 25(16): 2866-75.
3. Borbás T, Benkő B, Szabó I, Dalmadi B, Tihanyi K. (2006) Insulin in flavin-containing monooxygenase regulation. Flavin-flavin-containing monooxygenase and cytochrome P450 activities in experimental diabetes. Eur J Pharm Sci, 28(1-2): 51-58.
4. Borbás T, Zhang J, Cerny MA, Likó I, Cashman JR (2006) Investigation of structure and function of a catalytically efficient variant of the human flavin-containing monooxygenase form 3 (FMO3). Drug Metab and Dispos, 34: 1995-2002.
REFERENCES
1 Ziegler DM. Microsomal flavin-containing monooxygenase: oxygenation of nucleophilic nitrogen and sulphur compounds. In: Jakoby WB (Ed.), Enzymatic Basis of Detoxication. Academic Press, New York, 1980: 201-277.
2 Ziegler DM, Mitchell CH. (1972) Microsomal oxidases IV; Properties of a mixed function amine oxidase isolated from pig liver microsomes. Arch Biochem Biophys, 150: 116-125.
3 Miller JA, Kramer JW, Miller EC. (1960) The N-and-ring hydroxylation of 2 acetylaminofluorene during carcinogenesis in the rat. Cancer Res, 20: 950-962.
4 Ziegler DM, Jollow D, Cook DF. Properties of a purified liver microsomal mixed-function amine oxidase. In: Kamin, Henry (Ed.), Proceedings of the Third International Symposium on Flavins and Flavin-proteins. University Park Press, Butterworth and Co Ltd., Baltimore, London, 1971: 507-522.
5 Rettie AE, Fischer MB: Transformation Enzymes: Oxidative, Non-P450. In: Woolf TF (Ed.), Handbook of Drug Metabolism. Marcel Dekker Inc., New York, 1999: 132-151.
6 Cashman JR. Flavin monooxygenases. In: Ioannides C. (Ed.), Enzymes systems that Metabolise Drugs and Other Xenobiotics. John Wiley and Sons Ltd., 2002: 67-93.
7 Cashman JR. (1995) Structural and catalytic properties of the mammalian flavin-containing monooxygenase. Chem Res Toxicol, 8(2): 165-181.
8 Brunelle A, Bi YA, Lin J, Russel B, Luy L, Berkman C, Cashman JR. (1977) Characterization of two human flavin-containing monooxygenase (FORM3) enzymes expressed in Escherichia coli as maltose binding protein fusions. Drug Metab Dispos, 25(8): 1001-1007.
9Krueger SK, Williams DE. (2005) Mammalian flavin-containing monooxygenase:
structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther, 106: 357-387.
10 Cashman JR. In vitro metabolism: FMO and related oxygenations. In: Woolf TF (Ed.), Handbook of Drug Metabolism. Marcel Dekker Inc., Ann Arbor, 1999, 477-506.
11 Birkett DJ, MacKenzie PI, Veronese ME, Miners JO. (1993) In vitro approaches can predict human drug metabolism. Trends Pharmacol Sci, 14(8): 292-294.
12 Cashman JR. (2005) Some distinctions between flavin-containing and cytochrome P450 monooxygenases. Biochem Biophys Res Commun, 338: 599-604.
13Grothusen A, Hardt J, Brautigam L, Lang D, Böcker R. (1996) A convenient method to discriminate between cytochrome P450 enzymes and flavin-containing monooxygenases in human liver microsomes. Arch Toxicol, 71: 64-71.
14 Poulsen LL, Hyslop RM, Ziegler DM. (1979) S-oxygenation of N-substituted thioureas catalysed by the pig liver microsomal FAD-containing monooxygenase. Arch Biochem Biophys, 198: 78-88.
15 Larsen-Su S, Williams DE. (1996) Dietary indole-3-carbinol inhibits FMO activity and the expression of flavin-containing monooxygenase form 1 in rat liver and intestine.
Drug Metab Dispos, 24(9): 927-931.
16 Correira MA. Human and rat liver cytochromes P450: Functional markers, diagnostic inhibitor probes, and parameters frequently used in P450 studies (appendix). In: Ortiz de Montellano PR (Ed.), Cytochrome P450 structure, mechanism and biochemistry.
Kluwer Academic/Plenum Publishers, New York, 2005: 619-943.
17 Bhagwat SV, Bhamre S, Boyd MR, Ravindranath V. (1996) Further Characterization of rat brain flavin-containing monooxygenase. Metabolism of imipramine to its N-oxide. Biochem Pharmacol, 51(11): 1469-75.
18 Myers CR, Porgilsson B, Myers JM.(1997) Antibobies to a synthetic peptide that react with flavin-containing monooxygenase (HLFMO3) in human hepatic microsomes.
J Pharmacol Toxicol Methods, 37(2): 61-66.
19 Pike MG, Mays DC, Macomber DW, Lipsky JJ. (2001) Metabolism of disulfiram metabolite, S-methyl N,N-diethyldithiocarbamate, by flavin monooxygenase in human renal microsomes. Drug Metab Dispos, 29: 127-132.
20 Engler H, Taurog A, Nakashima T. (1982) Mechanism of inactivation of thyroid peroxidase by thioureylene drugs. Biochem Pharmacol, 31: 3801-3806.
21 Kedderis GL, Rickert DE. (1985) Loss of rat liver microsomal cytochrome P450 during methimazole metabolism. Role of flavin-containing monooxygenase. Drug Metab Dispos, 13: 58-61.
22Katchamart S, Stresser DM, Dehal SS, Kupfer D, Williams DE. (2000) Concurrent flavin-containing monooxygenase down-regulation and cytochrome P-450 induction by dietary indoles in rat: implications for drug-drug interactions. Drug Metab Dispos, 28:
930-936.
23 Lawton M, Cashman J, Cresteil T, Dolphin C, Alfarra A. (1994) A nomenclature for the mammalian flavin-containing monooxygenase gene family based on amino acid sequence identities. Arch Biochem Biophys, 308: 254-257.
24 Hines RN, Hopp KA, Franco J, Saeian K, Begun FP. (2002) Alternative processing of the human FMO6 gene renders transcripts incapable of encoding a functional flavin-containing monooxygenase. Mol Pharmacol, 62: 320-25.
25 Philips IR, Dolphin CT, Clair P, Hadley MR, Hutt AJ. (1995) The molecular biology of the flavin-containing monooxygenase of man. Chem Biol Interact, 96(1): 17-32.
26 Shephard EA, Dolphin CT, Fox ME, Povey S, Smith R, Phillips IR. (1993) Localization of genes encoding three distinct flavin-containing monooxygenase to human chromosome 1g. Genomics, 16: 85-89.
27 Dolphin CT, Riley JH, Smith RL, Shephard EA, Phillips IR. (1997) Structural organization of the human flavin-containing monooxygenase 3 gene (FMO3), the flavored candidate for Fish Odor Syndrome, determined directly from genomic DNA.
Genomics, 46: 260-267.
28 McCombie RR, Dolphin CT, Povey S, Phillips IR, Shepard E. (1996) Localization of human flavin-containing monooxygenase genes FMO2 and FMO5 to chromosome 1q.
Genomics, 1996, 34(3):426-9.
29 Wu RF, Ichikawa Y. (1994) Characteristic properties and kinetic amnalysis with neurotoxins of porcine FAD-containing monooxygenase. Biochem Biophys Acta, 1208:
204-210.
30 Ziegler DM. Flavin-containing monooxygenase family of isozymes. Abstract, Proc of the First International Workshop on Trimethylaminuria, Bethesda, MD, March 29-30., 1999.
31Ziegler DM. (2002) An overview of mechanism, substrate specificities and structure of FMOs. Drug Metab Rev, 34(3): 503-511.
32 Yeung CK, Lang DH, Thummel KE, Rettie AE. (2000) Immunoquantitation of FMO1 in human liver, kidney and intestine. Drug Metab Dispos, 28: 1107-1111.
33 Overby LH, Carver GC, Philpot RM. (1997) Quantitation and kinetic properties of hepatic microsomal and recombinant flavin-containing monooxygenases 3 and 5 from humans. Chem Biol Interact, 106: 29-45.
34 Cashman JR, Camp K, Fakharzadeh SS, Fenessey PV, Hines RN, Mamer OA, Mitchell SC, Preti G, Schlenk D, Smith RL, Tjoa SS, Williams DE, Yannicelli S. (2003) Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Curr Drug Metab, 4: 151-170.
35 Zhang J, Cashman JR. (2006) Quantitative analysis of FMO gene mRNA levels in human tissues. Drug Metab Dispos, 34: 19-26.
36 Cashman JR. (2000) Human flavin-containing monooxygenase: substrate specificity and role in drug metabolism. Curr Drug Metab, 1(2): 181-191.
37 Ripp SL, Itagaki K, Philpot RM, Elfarra AA. (1999) Species and sex differences in expression of flavin-containing monooxygenase form 3 in liver and kidney microsomes.
Drug Metab Dispos, 27(1): 46-52.
38 Cherrington NJ, Cao Y, Cherrington JW, Rose RL, Hodgson E. (1998) Physiological factors affecting protein expression of flavin-containing monooxygenases 1, 3 and 5.
Xenobiotica, 28(7): 673-682.
39 Kim YM, Ziegler DM. (2000) Size limit of thiocarbamides accepted as substrates by human flavin-containing monooxygenase 1. Drug Metab Dispos, 28: 1003-1006.
40 Cashman JR and Zhang J. (2006) Human flavin-monooxygenases. Annu Rev Pharmacol Toxicol, 46: 65-100.
41 Lin J, Cashman JR. (1997) Detoxication of tyramine by the flavin-monooxygenase:
stereoselective formation of the trans oxime. Chem Res Toxicol, 10: 842-52.
42 Yamada H, Baba T, Oguri K, Yoshimura H. (1988) The mammalian flavin-containing monooxygenases: molecular characterization and regulation of expression.
Biochem Pharmacol, 37(2): 368-370.
43 Lin J, Cashman JR. (1997) N-oxygenation of phenethylamine to the trans-oxime by adult human liver flavin-containing monooxygenase and retroreduction of phenethylamine hydroxylamine by human liver microsomes. J Pharmacol Exp Ther, 282(3): 1269-79.
44 Hadley MR, Svajdlenka E, Damani LA, Oldham HG, Tribe J, Camilleri P, Hutt AJ.
(1994) Species variability in the stereoselective N-oxidation of pargyline. Chilarity, 6(2): 91-7.
45 Kashiyama E, Yokoi T, Odomi M, Kamataki T. (1999) Stereoselective S-oxidation and reduction of flosequinan in rat. Xenobiotica, 29(8): 815-26.
46 Ripp SL, Itagaki K, Philpot RM, Elfarra AA. (1999) Methionine S-oxidation in human and rabbit liver microsomes: evidence for a high-affinity methionine S-oxidase activity that is distinct from flavin-containing monooxygenase 3. Arch Biochem Biophys, 367: 322-332.
47 Hines RN, Cashman JR, Philpot RM, Williams DE, Ziegler DM. (1994) The mammalian flavin-containing monooxygenases: molecular characterization and regulation of expression. Toxicol Appl Pharmacol, 125(1): 1-6.
48 Cashman JR, Akerman BR, Forrest SM, Treacy EP. (2000) Population-specific polymorphisms of the human FMO3 gene: significance for detoxication. Drug Metab Dispos, 28(2): 169-173.
49Lang DH, Rettie AE. (2000) In vitro evaluation of potential in vivo probes for human flavin-containing monooxygenase (FMO): metabolism of benzydamine and caffeine by FMO and P450 isoforms. Br J Clin Pharmacol, 50: 311-314.
50 Kawaji A, Ohara K, Takabatake E. (1993) An assay of flavin-containing monooxygenase activity with benzydamine N-oxidation. Anal Biochem, 214: 409-412.
51 Störmer E, Roots I, Brockmöller J. (2000) Benzydamine N-oxydation as an index reaction reflecting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity. Br J Clin Pharmacol, 50: 553-561.
52 Chasseaud LF, Catanese B. (1985) Pharmacokinetics of benzydamine. Int J Tissue React, 7: 195-204.
53 Park CS, Chung WG, Kang JH, Roh HK, Lee KH, Cha YN. (1999) Phenotyping of flavin-containing monooxygenase using caffeine metabolism and genotyping of FMO3 gene in a Korean population. Pharmacogenetics, 9(2): 155-164.
54 Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA. (1991) Aromatic hydrocarbon responsivness-receptor agonists generated from indole-3-carbinol in in vitro and in in vivo:comparison with 2,3,7,8-tetrachloro-dibenzo-p-dioxin. Proc Natl Acad Sci USA, 88: 9543-9547.
55 Cashman JR, Xiong Y, Lin J, Verhagen H, Poppel G, Bladeren PJ, Larsen-Su S, Willimams DE. (1999) In vitro and in vivo inhibition of human flavin-containing monooxygenase form 3 (FMO3) in the presence of dietary indoles. Biochem Pharmacol, 58: 1047-1055.
56 Katchamart S, Williams DE. (2001) Indole-3-modulation of hepatic monooxygenases CYP1A1, CYP1A2 and FMO1 in guinea pig, mouse and rabbit. Comp Biochem Physiol C Toxicol Pharmacol, 129: 377-384.
57 Ziegler DM. (1988) Flavin-containing monooxygenases: catalytic mechanism and substrate specificities. Drug Metab Rev, 19: 1-32.
58 Ziegler DM. (1990) Flavin-containing monooxygenases: enzymes adapted for multisubstrate specificity. Trends Pharmacol Sci, 11(8): 321-324.
59 Zhao Y, Christensen, Fankhauser C, Cashman JR, Cohen JD, Weigel D, Chory J.
(2001) A role for flavin monooxygenase-like enzymes in auxin biosynthesis. Science, 291: 306-309.
60 Suh JK, Poulsen LL, Ziegler DM, Robertus JD. (1999) Yeast flavin-containing monooxygenase generates oxidizing equivalents controlling protein folding in the endoplasmatic reticulum. Proc Natl Acad Sci USA, 96: 2687-2691.
61 Suh J, Robertus JD. (2000) Yeast FMO is induced by the unfolded protein response.
Proc. Natl. Acad. Sci. USA, 2000, 97:121-126.
62 Ziegler DM, Duffel MW, Poulsen LL. (1979) Studies on the nature and regulation of the cellular thio:disulphide potential. Ciba Found Symp, 72: 191-204.
63 Jeitner TM, Lawrence DA. (2001) Mechanisms for the cytotoxicity of cysteamine.
Toxicol Sci, 62: 57-64.
64 Khomenko T, Deng X, Sandor Z, Tarnawski AS, Szabo S. (2004) Cystemanine alters redox state, HIF-1α transcriptional interactions and reduces duodenal mucosal oxygenation: novel insight into the mechanisms of duodenal ulceration. Biochem Biophys Res Commun, 317: 121-127.
65 Hagen TM, Moreau R, Suh JH, Visioli F. (2002) Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-carnitine and/or lipoic acid. Ann N Y Acad Sci, 959: 491-507.
66 Cerny MA, Hanzlik RP. (2005) Cyclopropylamine in action of cytochrome P450: role of metabolite intermediate complexes. Biochem Biophys, 436: 265-275.
67 Rodriguez RJ, Buckholz CS. (2003) Hepatotoxicity of ketoconazole in Sprague Dawley rats: glutathione depletion, flavin-containing monooxygenases-mediated
68 Cashman JR. (2003) The role of flavin-containing monooxygenases in drug metabolism and development. Curr Opin Drug Discov Devel, 6(4): 486-493.
69 Ayesh R, Smith RL. (1990) Genetic polymorphism of trimethylamine N-oxidation.
Pharmacol Ther, 45: 387-401.
70 Treacy EP, Akerman BR, Chow LM, Youil R, Bibeau C, Lin J. (1998) Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet, 7: 839-45.
71 Mitchell SC, Smith RL. (2001) Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos, 29: 517-521.
72 Humbert JR, Hammond KB, Hathaway WE, Marcoux JG, O’Brien D. (1970) Trimethylaminuria: fish-odour syndrome. The Lancet, 4: 970-971.
73 Mitchell SC, Smith RL. (2003) Trimethylamine and odorous sweat. J Inherit Metab Dis, 26: 415-16.
74 Mitchell SC, Zhang AQ, Barrett T, Ayesh R, Smith RL. (1997) Studies on the dicontinous N-oxidation of trimethylamine among Jordanian, Ecuadorian and New-Guinean populations. Pharmacogenetics, 7: 45-50.
75 McConnell HW, Mitchel SC, Smith RL, Brewster M. (1997) Trimethylaminuria associated with seizures and behavioural disturbance: a case riport. Seizure, 6: 317-322.
76 Luo Z, Hines RN. (2001) Regulation of flavin-containing monooxygenase 1 expression by Ying Yang and Hepatic Nuclear Factors 1 and 4. Mol Pharmacol, 60:
1421-1430.
77 Luo Z, Hines RN. (1997) Further characterization of the major and minor rabbit FMO1 promoters and identification of both positive and negative distal regulatory elements. Arch Biochem Biophys, 346: 96-104.
78 El-Alfy, Larsen B, Schlenk D. (2002) Effect of cortisol and urea on flavin monooxygenase activity and expression in rainbow trout, Oncorhynchus mykiss. Mar Environ Res, 54: 275-278.
79Ryu SD, Yi HG, Cha YN, Kang JH, Kang JS, Jeon YC, Park HK, Yu TM, Lee JN, Park CS. (2004) Flavin-containing monooxygenase activity can be inhibited by nitric oxide-mediated S-nitrosylation. Life Sci, 75(21): 2559-72.
80 Kaderlik RK, Weser E, Ziegler DM. (1991) Selective loss of liver flavin-containing monooxygenase in rats on chemically defined diets. Prog Pharm Clin Pharm, 8(3): 95-103.
81Cashman JR, Lattard V, Lin J. (2004) Effect of total parenteral nutrition and choline on hepatic flavin-containing and cytochrome P450 monooxygenase activity in rats.
Drug Metab Dispos, 32: 222-229.
82 Dixit A and Roche TE. (1984) Spectrophotometric assay of the flavin-containing monooxygenase and changes in its activity in female mouse liver with nutritional and diurnal conditions. Archs Biochem Biophys, 238 (1): 50-63.
83 Brodfuehrer JI and Zannoni VG. (1986) Ascorbic acid deficiency and flavin-containing monooxygenase. Bichem Pharmacol, 35(4): 637-644.
84 Coecke S, Debast G, Phillips IR, Vercruysse A, Shepard EA, Rogiers V. (1998) Hormonal regulation of microsomal flavin-containing monooxygenase activity by sex steroids and growth hormone in co-cultured adult male rat hepatocytes. Biochem Pharmacol, 56: 1047-1051.
85 Dannan GA, Guengerich FP, Waxman DJ. (1986) Hormonal regulation of rat liver microsomal enzymes. J Biol Chem, 261: 10728-10735.
86 Hines RN, Cashman JR, Philpot RM, Williams DE, Ziegler DM. (1994) The mammalian flavin-containing monooxygenases: molecular characterisation and regulation of expression. Toxicol Appl Pharmacol, 125: 1-6.
87 Osimitz TG, Kulkarni AP. (1982) Oxidative metabolism of xenobiotics during pregnancy. Significance of microsomal flavin-containing monooxygenase. Biochem Biophys Res Commun, 109: 1164-1171.
88 Heinze E, Hlavica P and Kiese M. (1970) N-oxygenation of arylamines in microsomes prepared from corpra lutea of the cycle and other tissues of the pig.
Biochem Pharmacol, 19: 641-649.
89 Roderick E. McGrew. Diabetes Mellitus. In: Roderick E. McGrew (Ed.), Encyclopedia of medical history. Macmillan Press, London, 1985: 90-93.
90 Ádám V, Mandl J. A szénhidrátok anyagcseréje. In: Ádám V (Ed.), Orvosi biokémia.
Semmelweis Kiadó, Budapest, 1996: 76-120.
91 Tímár J. A szénhidrát-anyagcsere gyógyszertana. In: Fürst Zs (Ed.), Gyógyszertan.
Medicina Könyvkiadó Rt., Budapest, 1999: 742-757.
92 Dainith H, Stevenson IH, O’Malley K. (1976) Influence of diabetes mellitus on drug metabolism in man. Int J Clin Pharmacol, 13: 55-58.
93 Adithan C, Danda D, Swaminathan RP, Indhiresan J, Shasindran CH, Bapna JS, Chandrasekar S. (1988) Effect of type I diabetes mellitus on theophylline elimination.
Med Sci Res, 16: 427-428.
94 Adithan C, Sriram G, Swaminathan RP, Krishnan M, Bapna JS, Chandrasekar S.
(1989) Effect of type II diabetes mellitus on theophylline elimination. Int J Clin Pharmacol Ther Toxicol, 27: 258-260.
95 Gwilt PR, Nahhas RR, Tracewell WG. (1991) The effects of diabetes mellitus on pharmacokinetics and pharmacodynamics in humans. Clin Pharmacokinet, 20(6): 477-490.
96 Adithan C, Danda D, Shasindran CH, Bapna JS, Swaminathan RP, Chandrasekar S.
(1989) Differential effect of type I and type II diabetes mellitus on antyipyrine elimination. Meth and Find Exp Clin Pharmacol, 11(12): 755-758.
97 Matzke GR, Frye RF, Early JJ, Straka RJ, Carson SW. (2000) Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity. Pharmacotherapy, 20(2): 182-190.
98 Dajani RM, Kayyali S, Saheb SE, Birbari A. (1974) A study on the physiological disposition of acetophenetidin by the diabetic man. Comp Gen Pharmacol, 5:1-9.
99 Sotaniemi EA, Pelkonen O, Arranto AJ, Tapanainen P, Rautio A, Pasanen M. (2002) Diabetes and elimination of antipyrine in man: an analysis of 298 patients classified by type of diabetes, age, sex, duration of disease and liver involvement. Pharmacol Toxicol, 90: 155-160.
100 Zysset T, Wiwtholtz H. (1988) Differential effect of type I and type II diabetes on antipyrine disposition in man. Eur J Clin Pharmacol, 34: 369-375.
101 Takamura T, Shakurai M, Ota T, Ando H, Honda M, Kaneko S. (2004) Genes for systemic vascular complications are differentially expressed in the livers of type 2 diabetic patients. Diabetologia, 47: 638-647.
102 Elsner M, Guldbakke B, Tiedge M, Munday R, Lenzen S. (2000) Relative importance of transport and alkylation for pancreatic β-cell toxicity of streptozotocin.
Diabetologia, 43: 1528-1533.
103 Gruppuso PA, Boylan JM, Posner BI, Faure R, Braitigan DL. (1990) Hepatic protein phosphotyrosine phosphatase. Dephosphorylation of insulin receptor and epidermal growth factor receptors in normal and alloxan diabetic rats. J Clin Invest, 85: 1754-1760.
104 Dunn JS, Sheehan HL, McLethie NGB. (1943) Necrosis of islets of Langerhans produced experimentally. Lancet, 1: 484-487.
105 Arison RN, Ciaccio EI, Glitzer MS, Cassaro JA, Pruss MP. (1967) Light and electron microscopy of lesions in rats rendered diabetic with streptozotocin. Diabetes, 16: 51-56.
106 Dixon RL, Hart LG, Foust JR. (1961) The metabolism of drugs by liver microsomes from alloxan diabetic rats. J Pharmacol Exp Ther, 133: 7-11.
107 Dajani RM and Saheb SE. (1971) In vitro and in vivo studies of the metabolism of phenylbutazone in the alloxan rat and rabbit (Abstract). J Pharm Pharmacol, (Suppl) 23:
220S-221S.
108 Nishihata T, Yata N, Kamada A. (1979) Role of acetone bodies in the abnormal pharmacokinetic behaviour of chlorpropramide in alloxan diabetic rabbits. Chem Pharm Bull, 27: 1740-1746.
109 Dixon RL, Hart LG, Rogers LA, Fouts JR. (1963) The metabolism of drugs by liver microsomes from alloxan diabetic rats: long-term diabetes. J Pharmacol Exp Ther, 142:
312- 317.
110 Ackerman DM and Leibman KC. (1977) Effect of experimental diabates on drug metabolism in the rat. Drug Metab Dispos, 5(4): 405-410.
111 Rouer E, Lemoine A, Cresteil P, Rouet P, Leroux JP. (1987) Effects of genetic or chemically induced diabetes on imipramine metabolism. Drug Metab Dispos, 15(4):
524-528.
112 Reinke LA, Stohs SJ, Rosenberg H. (1978) Altered activity of hepatic mixed-function monooxygenase enzymes in streptozotocin-induced diabetic rats. Xenobiotica, 8(10): 611-619.
113 Barnett CR, Flatt PR, Ioannides C. (1994) Modulation of the rat hepatic cytochrome P450 composition by long-term streptozotocin-induced insulin-dependent diabetes. J Biochem Toxicol, 9(2): 63-69.
114 Yamazoe Y, Murayama N, Shimada M, Yamauchi K, Kato R. (1989) Cytochrome P450 in livers of diabetic rats: regulation by growth hormone and insulin. Arch Biochem Biophys, 268: 567-575.
115 Shimojo N, Ishizaki T, Imaoka S, Funae Y, Fujii S, Okuda K. (1993) Changes in amounts of cytochrome P450 isozymes and levels of catalytic activities in hepatic and renal microsomes of rats with streptozotocin-induced diabetes. Biochem Pharmacol, 46(4): 621-627.
116 Schenkman JB. (1991) Induction of diabetes and evaluation of diabetic state on P450 expression. Methods Enzymol, 206: 325-331.
117 Rouer E and Leroux JP. (1980) Liver microsomal cytochrome P-450 related monooxygenase activities is genetically hyperglycemic (ob/ob and db/db) and lean streptozotocin-treated mice. Biochem Pharmacol, 29: 1959-1962.
118 Rouer E, Rouet P, Delpech M, Leroux JP. (1988) Purification and comparison of liver microsomal flavin-containing monooxygenase from normal and streptozotocin-diabetic rats. Biocheml Pharmacol, 37(18): 3455-3459.
119 Wang T, Shankar K, Ronis MJJ, Mehendale HM. (2000) Potentiation of thioacetamide liver injury in diabetic rats is due to induced CYP2E1. J Pharmacol Exp Ther 294: 473-479.
120 Cavagnaro J, Rauckman EJ, Rosen GM. (1981) Estimation of FAD monooxygenase in microsomal preparations. Anal Biochem, 118: 204-211.
121 Holloway CT, Garfield SA. (1981) Effect of diabetes and insulin replacement on the lipid on properties of hepatic smooth endoplasmic reticulum. Lipids, 16: 525-532.
122 Rouer E, Lemoine A, Cresteil P, Rouet P, Leroux JP. (1987) Effects of genetic or chemically induced diabetes on imipramine metabolism. Drug Metab Dispos, 15(4):
524-528.
123 Barnett CR, Wilson J, Wolf CR, Flatt PR, Ioannides C. (1992) Hyperinsulinaemia causes a preferential increase in hepatic P4501A2 activity. Biochem Pharmacol, 43(6):
1255-1261.
124 Woodcroft KJ, Novak RF. (1999) Insulin differentially affects xenobiotic-enchanced, cytochrome P450 (CYP)2E1, CYP2B, CYP3A and CYP4A expression in primary cultured rat hepatocytes. J Pharmacol Exp Ther, 289: 1121-1127.
125 Pike MG, Martin YN, Mays DC, Benson LM, Naylor S, Lipsky JJ. (1999) Roles of FMO and P450 in the metabolism in human liver microsomes of S-methyl-N,N-diethyldithiocarbamate, a dilsulfiram metabolite. Alcohol Clin Exp Res, 23(7): 1173-1179.
126 Lowry OH, Rosebrough NJ, Farr AL and Randall RJ. (1951) Protein measurement with the folin phenol reagent. J Biol Chem, 193(1): 265-275.
127 Greim H. (1970) Synthesesteigerung und abbauhemmung bei der vermehrung der mikrosomalen cytochrome P450 und b-5 durch pehenobarbital. Naunyn-Schmiedebergs Arch Pharmak, 266: 261-275.
128 Burke MD. (1985) Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues:
A series of substrates distinguish between different induced cytochromes P450.
Biochem Pharmacol, 34: 33-37.
129 Nash T. (1953) The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem J, 55(3): 416-21.
130 Reinke LA, Moyer MJ. (1985) Para-nitrophenol hydroxylation: a microsomal oxidation which is highly inducible by ethanol. Drug Metab Dispos, 13: 548-552.
131 Anderson CD, Wang J, Kumar JN, McMilan JM, Walle UK, Walle T. (1995) Dexamethasone induction of taxol metabolism in the rat. Drug Metab Dispos, 23: 1286-1291.
132 Woodcroft KJ, Hafner MS, Novak RF. (2002) Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. Hepatology, 35(2): 263-273.
133 Barnett CR, Gibson GG, Wolf CR, Flatt PR, Ioannides C. (1990) Induction of cytochrome P450III and P450IV family proteins in streptozotocin-induced diabetes.
Biochem J, 286: 765-769.
134 Bellward GD, Chang T, Rodriguez B, McNeill JH, Mains S, Ryan DE, Levin W, Thomas PE. (1988) Hepatic cytochrome P450 induction in the spontaneously diabetic BB rat. Mol Pharmacol, 33: 140-143.
135 Ádám V, Faragó A. Extracelluláris jelek receptorai és a jelátviteli mechanizmusok.
In: Ádám V (Ed.), Orvosi biokémia. Semmelweis Kiadó, Budapest, 1996: 371-415.
136 Schenkman JB, Jansson I. (2003) The many roles of cytochrome b5. Pharmacol Ther, 97(2): 139-152.
137 Eck MG, Wynn JO, Carter WJ, Faas FH. (1979) Fatty acid desaturation in experimental diabetes mellitus. Diabetes, 28(5): 479-485.
8 PUBLICATIONS
Publications the dissertation based on
1. Balázs Dalmadi, János Leibinger, Szabolcs Szeberényi, Tímea Borbás, Sándor Farkas, Zsolt Szombathelyi and Károly Tihanyi: Identification of metabolic pathways involved in the biotransformation of tolperisone by human microsomal enzymes. Drug Metabolism and Disposition, 31:631-636, 2003
2. Éva Szökő, Tamás Tábi, Tímea Borbás, Balázs Dalmadi, Károly Tihanyi and Kálmán Magyar: Assessment of the N-oxidation of deprenyl, methamphetamine and amphetamine enantiomers by chiral capillary electrophoresis; an in vitro metabolism study. Electrophoresis, 25(16): 2866-75, 2004
3. Tímea Borbás, Bernadett Benkő, Imola Szabó, Balázs Dalmadi, Károly Tihanyi:
Insulin in flavin-monooxygenase regulation. Flavin-containing monooxygenase and cytochrome P450 activities in experimental diabetes. European Journal of Pharmaceutical Sciences, 28(1-2): 51-58, 2006
4. Borbás T, Zhang J, Cerny MA, Likó I, Cashman JR: Investigation of structure and function of a catalytically efficient variant of the human flavin-containing monooxygenase form 3 (FMO3). Drug Metabolism and Disposition, 34: 1995-2002, 2006
Other publications
1. Borbás Tímea, Hegyesi Hargita: Huntington chorea: genetika és biokémia, diagnosztika és terápia. Acta Pharmaceutica Hungarica, 72(2):127-36, 2002
Oral presentations
1. Dalmadi Balázs, Leibinger János, Szeberényi Szabolcs, Borbás Tímea, Pásztor Gabriella, Farkas Sándor, Tihanyi Károly: A tolperisone in-vitro metabolikus vizsgálata. 30 ÉVES JUBILEUMI FARMAKOKINETIKA ÉS GYÓGYSZERMETABOLIZMUS SZIMPÓZIUM, 2002. április 4-6., Mátraháza
2. Dalmadi Balázs, Leibinger János, Szeberényi Szabolcs, Borbás Tímea, Pásztor Gabriella, Farkas Sándor, Tihanyi Károly: A tolperisone in-vitro metabolikus vizsgálata. VI. CLAUDER OTTÓ EMLÉKVERSENY, 2002. szeptember 27-28.,
3. Borbás Tímea, Dalmadi Balázs, Szeberényi Szabolcs, Leibinger János, Beke Gyula, Tihanyi Károly: Korreláció az egyes citokróm P450 izoenzimek és a flavin-monooxigenáz aktivitása között. VI. CLAUDER OTTÓ EMLÉKVERSENY, 2002.
szeptember 27-28., Budapest
4. Borbás Tímea, Benkő Bernadett, Dalmadi Balázs, Szeberényi Szabolcs, Leibinger János, Beke Gyula, Tihanyi Károly: Koexpresszió CYP és FMO izoformák között enzimatikus szinten, humán és patkány mikroszómán vizsgálva. Ph.D.
TUDOMÁNYOS NAPOK 2003, 2003. április 10-11., Budapest
5. Benkő Bernadett, Borbás Tímea, Dalmadi Balázs, Szeberényi Szabolcs, Leibinger János, Tihanyi Károly: Intesztinális gyógyszermetabolizmus jelentősége és stabil citokróm P450 tartalmú mikroszóma preparálása patkány vékonybélből. Ph.D.
TUDOMÁNYOS NAPOK 2003, 2003. április 10-11., Budapest
6. Rapavi Erika, Szeberényi Szabolcs, Borbás Tímea, Lugasi Andrea, Szentmihályi Klára, Pallai Zsolt, Kurucz Tímea, Kocsis Ibolya, Taba Gabriella, Blázovics Anna:
Természetes eredetű gyógyszer hatása a szöveti redox-státuszra patkányban.
MAGYAR SZABADGYÖK-KUTATÓ TÁRSASÁG II. KONFERENCIÁJA, 2003.
szeptember 25-27., Sopron
7. Rapavi Erika, Kocsis Ibolya, Szentmihályi Klára, Lugasi Andrea, Fehér Erzsébet, Bányai Éva, Rhenzo Gonzalez-Cabello, Székely Edit, Szeberényi Szabolcs, Borbás Tímea, Pallai Zsolt, Kurucz Tímea, Balázs Andrea, Czinner Erika, Héthelyi Éva, Hagymási Krisztina, Bárkovics Sarolta, Pintér Edina, Bíró Erzsébet, Fehér János, Blázovics Anna: Újabb adatok a természetes hatóanyagok in vitro és in vivo hatásmechanizmusának megértéséhez. SZÉCHENYI SZIMPÓZIUM, 2004. március 10., Budapest
8. Borbás Tímea, Benkő Bernadett és Tihanyi Károly: Streptozotocinnal kiváltott diabétesz hatása a hepatikus gyógyszermetabolizmusra patkányban. Ph.D.
TUDOMÁNYOS NAPOK 2004. április 8-9., Budapest
9. Benkő Bernadett, Borbás Tímea és Tihanyi Károly: Streptozotocinnal kiváltott diabétesz hatása az intesztinális gyógyszermetabolizmusra patkányban. Ph.D.
TUDOMÁNYOS NAPOK 2004. április 8-9., Budapest