Abstract:
Aminoazo dyes and other hepatocarcinogenic substances inhibit glucocorticoid-mediated induction of adaptive enzymes, including tyrosine aminotransferase (TAT), in mouse and rat liver.
There is a specific relationship between the effect of a carcinogen on TAT induction and its liver carcinogenicity in animals. Presuming tumor development being initiated not directly by the chemicals employed but their metabolically activated derivatives, the question arises whether TAT induction is inhibited by carcinogen metabolites or by their parent compounds. The goal of this paper is to shed some light on the issue. Mouse strains differing in the sensitivity to both carcinogenic and antiglucocorticoid (TAT induction inhibitory) effects of the mouse-specific carcinogen ortho- aminoazotoluene (OAT) underwent a set of experimental procedures: ablation of gonadal and adrenal glands, administration of inhibitors (CoCl2, pentachlorophenol), inducers (3,4- benzopyrene, Aroclor 1254, 20-methylcholanthrene) of xenobiotic-metabolizing enzyme activities, and others. The results unequivocally confirm that glucocorticoid induction of TAT activity in mouse liver is inhibited by activated metabolite(s) of OAT rather than by its intact molecules. In contrast, nonspecific genotoxic agents such as cyclophosphamide and cisplatin exert no effect on TAT induction by glucocorticoids. The wide occurrence (practically in each TAT-expressing hepatocyte) and rapidly reversible inhibition of enzyme induction by the carcinogen point to the epigenetic nature of this phenomenon.
About The Authors:
V. I. Kaledin. Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia; Russian Federation
N. A. Popova. Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia; Russian Federation
L. F. Gulyaeva. Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Russia, Russian Federation
References:
1. Baginskaya N.V., Il’nitskaya S.I., Nikitenko E.V., Kaledin V.I. Promotiruyushchee vliyanie orto-aminoazotoluola na gepatokantserogenez soprovozhdaetsya usileniem vospalitel’nykh i proliferativnykh protsessov v tkani pecheni i snizheniem kontsentratsii svobodnogo tiroksina v krovi. Byul. eksperim. biol. meditsiny. 2007;144:672-675.
2. Vilenchik M.M. Zakonomernosti molekulyarno-geneticheskogo deĭstviya khimicheskikh kantserogenov. M.: Nauka, 1977.
3. Kaledin V.I., Glazko T.T., Zakharova N.P. Narushenie induktsii tirozinaminotransferazy v pecheni mysheĭ, poluchavshikh o-aminoazotoluol. Dokl. AN SSSR. 1979;244:233-237.
4. Kaledin V.I., Gulyaeva L.F., Vavilin V.A., Makarova S.M., Morozkova T.S., Rikhter V.A. Aktivnost’ fermentov metabolizma ksenobiotikov v pecheni chuvstvitel’nykh k gepatokantserogennomu deĭstviyu orto-aminoazotoluola mysheĭ liniĭ SWR i C3HA i rezistentnykh — AKR i CC57BR. Eksperim. onkologiya. 1999;21:18-23.
5. Kaledin V.I., Zakharova N.P. Vliyanie gepatokantserogennykh soedineniĭ na gormonal’nuyu induktsiyu tirozinaminotransferazy v pecheni chuvstvitel’nykh i rezistentnykh zhivotnykh. Issledovaniya po induktsii i metastazirovaniyu zlokachestvennykh opukholeĭ u eksperimental’nykh zhivotnykh. Novosibirsk: ITsiG, 1984:146-185.
6. Kaledin V.I., Il’nitskaya S.I. Tormozhenie metabolizma stimuliruet, a aktivatsiya metabolizma ingibiruet kantserogennoe deĭstvie orto-aminoazotoluola na pechen’ mysheĭ. Vopr. onkologii. 2011;7:216-220.
7. Kaledin V.I., Il’nitskaya S.I., Baginskaya N.V. Ingibiruyushchee vliyanie o-aminoazotoluola na gepatokantserogennoe deĭstvie dietilnitrozamina pri sovmestnom primenenii u mysheĭ. Vopr. onkologii. 2010;56(2):196-200.
8. Kaledin V.I., Pakharukova M.Yu., Pivovarova E.N., Kropachev K.Yu., Baginskaya N.V., Vasil’eva E.D., Il’nitskaya S.I., Nikitenko E.V., Kobzev V.F., Merkulova T.I. Sootvetstvie mezhdu gepatokantserogennym deĭstviem estragola i ego vliyaniem na glyukokortikoidnuyu induktsiyu pechen’spetsifichnykh fermentov i aktivnost’ faktorov transkriptsii v pecheni mysheĭ i krys. Biokhimiya. 2009;74:466-475.
9. Kaledin V.I., Serova I.A., Tsellarius Yu.G., Semenova L.A., Alekseeva G.V. Mezhlineĭnye razlichiya po chastote spontannykh i indutsirovannykh orto-aminoazotoluolom opukholeĭ u mysheĭ. Issledovaniya po induktsii i metastazirovaniyu zlokachestvennykh opukholeĭ u eksperimental’nykh zhivotnykh. Novosibirsk: ITsiG, 1984:98-123.
10. Morozkova T.S., Zhukova N.A., Semenov D.E., Popova N.A. Myshi linii PT/Y chuvstvitel’ny k ingibiruyushchemu glyukokortikoidnuyu induktsiyu tirozinaminotransferazy i gepatokkantserogennomu deĭstviyu orto-aminoazotoluola. Byul. eksperim. biol. meditsiny. 2014;158(12):757-761.
11. Ovchinnikova L.P., Bogdanova L.A., Kaledin V.I. Mutagennaya aktivatsiya snizhaet kantserogennost’ orto-aminoazotoluola dlya pecheni mysheĭ. Byul. eksperim. biol. meditsiny. 2012;154(11):623-628.
12. Turusov V.S., Belitskiĭ G.A., Pylev L.N., Koblyakov V.A. Mekhanizmy deĭstviya i klassifikatsiya khimicheskikh kantserogenov. Kantserogenez. M.: Meditsina, 2004:204-225.
13. Andersen R.A., Raina P.N., Milholland R.J. Altered responses to cortisol in precancerous liver. Oncologia. 1966;20:153-166.
14. Delclos K.B., Miller E.C., Miller J.F., Liem A. Sulfuric acid esters as major ultimate electrophilic metabolites of 4-aminoazobenzene and its N-methyl derivatives in infant male C57BL /6J × C3H/HeJ F1 (B6C3F1.mice. Carcinogenesis. 1986;7:277-287.
15. Hamilton J.W., Louis C.A., Doherty K.A., Hunt S.R., Reed M.J., Treadwell M.D. Preferential alteration of inducible gene expression in vivo by carcinogens that induce bulky DNA lesions. Mol. Carcinog. 1993;8:34-43.
16. Horikoshi N., Tashiro F., Tanaka N., Ueno Y. Modulation of hormonal induction of tyrosine aminotransferase and glucocorticoid receptor by aflatoxin B1 and sterigmatocystin in Reuber hepatoma cells. Cancer Res. 1988;48:5188-5192.
17. Kizer D.E., Cox B., Howel B.A., Shirley B.C. Effect of hepatocarcinogens on hepatocyte DNA synthesis and cortisone induction of tryptophaneoxygenase. Cancer Res. 1969;29:2039-2046.
18. Kropachev K.Yu., Kaledin V.I., Kobzev V.F., Timofeeva O.A., Ilnitskaya S.I., Vasilyeva E.D., Plisov C.Y., Richkova N.A., Filipenko M.L., Merkulova T.I. Involvement of transcription factor HNF3γ in the effect of o-aminoazotoluene on glucocorticoid induction of tyrosine aminotransferase in mice sensitive to its hepatocarcinogenic action. Mol. Carcinog. 2001;31:10-15.
19. Merkulova T.I., Kropachev K.Yu., Timofeeva O.A., Vasiliev G.V., Levashova Z.B., Ilnitskaya S.I., Kobzev V.F., Pakharukova M.Y., Bryzgalov L.O., Kaledin V.I. Species-specific effects of the hepatocarcinogens 3′-methyl-4-dimethyl-aminoazobenzene and orthoaminoazotoluene in mouse and rat liver. Mol. Carcinog. 2005; 44:223-232.
20. Mikhailova O.N., Vasyunina E.A., Ovchinnikova L.P., Timofeeva O.A., Filipenko M.L., Kaledin V.I. O-aminoazotoluene does induce the enzymes of its own metabolism in mouse liver. Toxicology. 2005;211:132-138.
21. Miller M.S., Buzard G.S., McDowell A.E. In vivo inhibition of glucocorticoid-inducible gene expression by dimethylnitrosamine in rat liver. Biochen. Pharmacol. 1993;45:1465-1470.
22. Ohmi R., Bhargava M., Arias I.M. Binding of 3′-methyl-N,N-dimethyl-4-aminoazobenzene metabolites to rat liver cytosol proteins and ligandin subunits. Cancer Res. 1981;41:3461-3464.
23. Testa B., Jenner P. Inhibitors of cytochrome P450s and their mechanism of action. Drug Metab. Rev. 1981;12:1-117.
24. Timofeeva O.A., Eremeev A.V., Goloshchapov A., Kalashnikova E., Ilnitskaya S.I., Setkov N.A., Kobzev V.F., Buzard G.S., Filipenko M.L., Kaledin V.I., Merkulova T.I. Effect of o-aminoazotoluene on liver regeneration and p53 activation in mice susceptible and resistant to hepatocarcinogenesis. Toxicology. 2008;254: 91-96.
25. Warwick G.P., Roberts J.J. Persistent binding of butter yellow metabolites to rat liver DNA. Nature. 1967;215:1206-1207.
26. Wogan G.N., Friedman M.A. Inhibition by aflatoxin B1 of hydrocortisone induction of rat liver tryptophan pyrrolase and tyrosine aminotransferase. Arch. Bioch. Biophys. 1968;128:509-516.
