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Hormonal mechanisms of sex differentiation of the liver: the modern conception and problems

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Abstract

The level of thousands of genes expression in the liver is differentiated on the basis of sexual dimorphism that affects the frequency of appearance of different pathological forms. The main hormonal factors of the liver’s sex differentiation are sex steroids and growth hormone. The impulsive and close to continuous secretion character of growth hormone in male and female individuals may have effects on masculinization or feminization processes, accordingly. The mechanism of decoding the growth hormone’s secretion pattern by liver cells is not known. Some genes in the liver with the expression of sex differentiated genes, have so called memory of gender, which is created, probably, during early postnatal ontogenesis with involvement of both androgens and growth hormone. The physical transporter of this memory is not known. The possible molecular mechanisms of various effects based on sex differentiation in liver have been described in this survey, including unique cases of determining the role of the growth hormone’s pattern and permissive function of the growth hormone concerning the direct effect of sex steroids to hepatocytes.

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References

  • Agrawal, A.K. and Shapiro, B.H., Differential Expression of Gender-Dependent Hepatic Isoforms of Cytochrome P450 by Pulse Signals in the Circulating Masculine Episodic Growth Hormone Profile of the Rat, J. Pharmacol. Exp. Ther., 2000, vol. 292, no. 1, pp. 228–237.

    PubMed  CAS  Google Scholar 

  • Agrawal, A.K. and Shapiro, B.H., Intrinsic Signals in the Sexually Dimorphic Circulating Growth Hormone Profiles of the Rat, Mol. Cell. Endocrinol., 2001, vol. 173, nos. 1–2, pp. 167–181.

    Article  PubMed  CAS  Google Scholar 

  • Ahlgren, R., Norstedt, G., Baumbach, W.R., et al., Hormonal Regulation of the Female Enriched GH Receptor/Binding Protein MRNA in Rat Liver, J. High Resolut. Chromatogr. Chromatogr. Commun., 1995, vol. 113, no. 1, pp. 11–17.

    CAS  Google Scholar 

  • Ahluwalia, A., Clodfelter, K.H., and Waxman, D.J., Sexual Dimorphism of Rat Liver Gene Expression: Regulatory Role of Growth Hormone Revealed by Deoxyribonucleic Acid Microarray Analysis, Mol. Endocrinol., 2004, vol. 18, no. 3, pp. 747–760.

    Article  PubMed  CAS  Google Scholar 

  • Alvaro, D., Alpini, G., Onori, P., et al., Estrogens Stimulate Proliferation of Intrahepatic Biliary Epithelium in Rats, Gastroenterology, 2000, vol. 119, no. 6, pp. 1681–1691.

    Article  PubMed  CAS  Google Scholar 

  • Alvaro, D., Mancino, M.G., Onori, P., et al., Estrogens and the Pathophysiology of the Biliary Tree, World J. Gastroenterol., 2006, vol. 12, no. 22, pp. 3537–3545.

    PubMed  CAS  Google Scholar 

  • Astapova, I.I, Yakovenko, A.R, Shchelkunova, T.A, et al., in Proc. Int. Symp. “Current Problems of Molecular Genetics and Cell Biology”, Georgiev, G.P., et al., Eds., Moscow, 2000, pp. 182–188.

  • Astapova, I.I., Shchelkunova, T.A., Morozov, I.A., et al., Localization of a Site for Interaction with Hepatic Male-Specific Proteins in Two Rat Estrogen Sulfotransferase Genes, Biokhimiya, 2003, vol. 68, no. 4, pp. 494–500.

    Google Scholar 

  • Astapova, I.I., Smirnov, A.N., and Rubtsov, P.M., PCR Amplification and Structural Analysis of Two Paralogous Rat Estrogen Sulfotransferase Genes Mol. Biol. (Moscow), 2002, vol. 36, no. 4, pp. 635–642.

    CAS  Google Scholar 

  • Astapova, I.I., Yakovenko, A.R., Shchelkunova, T.A., et al., Cloning and Preliminary Characterization of the Rat Estrogen Sulfotransferase Gene 5′-Region, Mol. Biol. (Moscow), 1999, vol. 33, no. 3, pp. 392–397.

    CAS  Google Scholar 

  • Babasyan, S.A., Astapova, I.I., Sverdlova, P.S., et al., Induction of the Synthesis of Female-specific Growth Hormone Receptor mRNA Variants in Male Rat Liver, Mol. Biol. (Moscow), 1998, vol. 32, no. 5, pp. 830–831.

    Google Scholar 

  • Björnström, L. and Sjöberg, M., Mutations in the Estrogen Receptor DNA-Binding Domain Discriminate between the Classical Mechanism of Action and Cross-Talk with Stat5b and Activating Protein 1 (AP-1), J. Biol. Chem., 2002, vol. 277, no. 50, pp. 48479–48483.

    Article  PubMed  Google Scholar 

  • Bogorad, R.L., Ostroukhova, T.Y., Orlova, A.N., et al., Long Isoform of Prolactin Receptor Predominates in Rat Intrahepatic Bile Ducts and Further Increases under Obstructive Cholestasis, J. Endocrinol., 2006, vol. 188, no. 2, pp. 345–354.

    Article  PubMed  CAS  Google Scholar 

  • Bogorad, R.L., Ostroukhova, T.Yu., Orlova, A.N., et al., Prolactin Receptors in Rat Cholangiocytes: Regulation of Level and Isoform Ratio is Sex Independent, Biokhimiya, 2006, vol. 71, no. 2, pp. 229–236.

    Google Scholar 

  • Bogorad, R.L., Zenkova, T.Yu., Rubtsov, P.M., et al., Influence of Obstructive Cholestatis and Sex Hormones on the Ratio of mRNA of Two Alternative Prolactin Receptor Isoforms in Rat Hepatocytes, Biokhimiya, 2004, vol. 69, no. 10, pp. 1371–1380.

    Google Scholar 

  • Böttner, M., Christoffel, J., Jarry, H., et al., Effects of Long-Term Treatment with Resveratrol and Subcutaneous and Oral Estradiol Administration on Pituitary Function in Rats, J. High Resolut. Chromatogr. Chromatogr. Commun., 2006, vol. 189, no. 1, pp. 77–88.

    Google Scholar 

  • Bourdeau, V., Deschênes, J., Laperrière, D., et al., Mechanisms of Primary and Secondary Estrogen Target Gene Regulation in Breast Cancer Cells, Nucleic Acids Res., 2008, vol. 36, no. 1, pp. 76–93.

    Article  PubMed  CAS  Google Scholar 

  • Bowman, R.E., Maclusky, N.J., Diaz, S.E., et al., Aged Rats: Sex Differences and Responses to Chronic Stress, Brain Res., 2006, vol. 1126, no. 1, pp. 156–166.

    Article  PubMed  CAS  Google Scholar 

  • Brown, R.J., Adams, J.J., Pelekanos, R.A., et al., Model for Growth Hormone Receptor Activation Based on Subunit Rotation within a Receptor Dimmer, Nat. Struct. Mol. Biol., 2005, vol. 12, no. 9, pp. 814–821.

    Article  PubMed  CAS  Google Scholar 

  • Brzica, H., Breljak, D., Krick, W., et al., The Liver and Kidney Expression of Sulfate Anion Transporter sat-1 in Rats Exhibits Male-Dominant Gender Differences, Pflugers Arch., 2009, vol. 457, no. 6, pp. 1381–1392.

    Article  PubMed  CAS  Google Scholar 

  • Buckley, D.B. and Klaassen, C.D., Mechanism of Gender-Divergent UDP-Glucuronosyltransferase MRNA Expression in Mouse Liver and Kidney, Drug Metab. Dispos., 2009, no. 4, pp. 834–840.

  • Cao, J., Gowri, P.M., Ganguly, T.C., et al., PRL, Placental Lactogen, and GH Induce NA(+)/Taurocholate-Cotransporting Polypeptide Gene Expression by Activating Signal Transducer and Activator of Transcription-5 in Liver Cells, Endocrinology, 2001, vol. 142, no. 10, pp. 4212–4222.

    Article  PubMed  CAS  Google Scholar 

  • Carroll, J.S. and Brown, M., Estrogen Receptor Target Gene: an Evolving Concept, Mol. Endocrinol., 2006, vol. 20, no. 8, pp. 1707–1714.

    Article  PubMed  CAS  Google Scholar 

  • Carter-Su, C., Schwartz, J., and Smit, L.S., Molecular Mechanism of Growth Hormone Action, Annu. Rev. Physiol., 1996, vol. 58, pp. 187–207.

    Article  PubMed  CAS  Google Scholar 

  • Chen, L., Thung, S.N., and Woo, S.L., Metabolic Basis of Sexual Dimorphism in PKU Mice after Genome-Targeted PAH Gene Therapy, Mol. Ther., 2007, vol. 15, no. 6, pp. 1079–1085.

    PubMed  CAS  Google Scholar 

  • Chen, P.H., Tsao, Y.P., Wang, C.C., et al., Nuclear Receptor Interaction Protein, a Coactivator of Androgen Receptors (AR), is Regulated by AR and Sp1 to Feed Forward and Activate Its Own Gene Expression through AR Protein Stability, Nucleic Acids Res., 2008, vol. 36, no. 1, pp. 51–66.

    Article  PubMed  CAS  Google Scholar 

  • Cheng, X., Maher, J., Lu, H., et al., Endocrine Regulation of Gender-Divergent Mouse Organic Anion-Transporting Polypeptide (Oatp) Expression, Mol. Pharmacol., 2006, vol. 70, no. 4, pp. 1291–1297.

    Article  PubMed  CAS  Google Scholar 

  • Cheung, L., Andersen, M., Gustavsson, C., et al., Hormonal and Nutritional Regulation of Alternative CD36 Transcripts in Rat Liver—A Role for Growth Hormone in Alternative Exon Usage, BMC Mol. Biol., 2007, vol. 8, p. 60.

    Article  PubMed  CAS  Google Scholar 

  • Choi, H.K. and Waxman, D.J., Growth Hormone, but not Prolactin, Maintains Low-Level Activation of STAT5a and STAT5b in Female Rat Liver, Endocrinology, 1999, vol. 140, no. 11, pp. 5126–5135.

    Article  PubMed  CAS  Google Scholar 

  • Choi, H.K. and Waxman, D.J., Plasma Growth Hormone Pulse Activation of Hepatic JAK-STAT5 Signaling: Developmental Regulation and Role in Male-Specific Liver Gene Expression, J. High Resolut. Chromatogr. Chromatogr. Commun., 2000, vol. 141, no. 9, pp. 3245–3255.

    CAS  Google Scholar 

  • Chowen, J.A., Frago, L.M., and Argente, J., The Regulation of GH Secretion by Sex Steroids, Eur. J. Endocrinol., 2004, vol. 151.

  • Clodfelter, K.H., Holloway, M.G., Hodor, P., et al., Sex-Dependent Liver Gene Expression is Extensive and Largely Dependent upon Signal Transducer and Activator of Transcription 5b (STAT5b): STAT5b-Dependent Activation of Male Genes and Repression of Female Genes Revealed by Microarray Analysis, Mol. Endocrinol., 2006, vol. 20, no. 6, pp. 1333–1351.

    Article  PubMed  CAS  Google Scholar 

  • Clodfelter, K.H., Miles, G.D., Wauthier, V., et al., Role of STAT5a in Regulation of Sex-Specific Gene Expression in Female but not Male Mouse Liver Revealed by Microarray Analysis, Physiol. Genomics, 2007, vol. 31, no. 1, pp. 63–74.

    Article  PubMed  CAS  Google Scholar 

  • Cui, T.X., Kwok, R., and Schwartz, J., Cooperative Regulation of Endogenous CAMP-Response Element Binding Protein and CCAAT/Enhancer-Binding Protein Beta in GH-Stimulated C-Fos Expression, J. Endocrinol., 2008, vol. 196, no. 1, pp. 89–100.

    Article  PubMed  CAS  Google Scholar 

  • Delesque-Touchard, N., Park, S.H., and Waxman, D.J., Synergistic Action of Hepatocyte Nuclear Factors 3 and 6 on CYP2C12 Gene Expression and Suppression by Growth Hormone-Activated STAT5b. Proposed Model for Female Specific Expression of CYP2C12 in Adult Rat Liver, J. Biol. Chem., 2000, vol. 275, no. 44, pp. 34173–34182.

    Article  PubMed  CAS  Google Scholar 

  • Demyan, W.F., Song, C.S., Kim, D.S., et al., Estrogen Sulfotransferase of the Rat Liver: Complementary DNA Cloning and Age- and Sex-Specific Regulation of Messenger RNA, Mol. Endocrinol., 1992, vol. 6, no. 4, pp. 589–597.

    Article  PubMed  CAS  Google Scholar 

  • Dhir, R.N., Dworakowski, W., Thangavel, C., et al., Sexually Dimorphic Regulation of Hepatic Isoforms of Human Cytochrome P450 by Growth Hormone, J. Pharmacol. Exp. Ther., 2006, vol. 316, no. 1, pp. 87–94.

    Article  PubMed  CAS  Google Scholar 

  • Dhir, R.N., Thangavel, C., and Shapiro, B.H., Attenuated Expression of Episodic Growth Hormone-Induced CYP2C11 in Female Rats Associated with Suboptimal Activation of the Jak2/Stat5B and Other Modulating Signaling Pathways, Drug Metab. Dispos., 2007, vol. 35, no. 11, pp. 2102–2110.

    Article  PubMed  CAS  Google Scholar 

  • Donohue, T.M., Curry-McCoy, T.V., Nanji, A.A., et al., Lysosomal Leakage and Lack of Adaptation of Hepatoprotective Enzyme Contribute to Enhanced Susceptibility to Ethanol-Induced Liver Injury in Female Rats, Alcohol Clin. Exp. Res., 2007, vol. 31, no. 11, pp. 1944–1952.

    Article  PubMed  CAS  Google Scholar 

  • Edinger, R.S., Mambo, E., and Evans, M.I., Estrogen-Dependent Transcriptional Activation and Vitellogenin Gene Memory, Mol. Endocrinol., 1997, vol. 11, no. 13, pp. 1985–1993.

    Article  PubMed  CAS  Google Scholar 

  • Endo, M., Takahashi, Y., Sasaki, Y., et al., Novel Gender-Related Regulation of CYP2C12 Gene Expression in Rats, Mol. Endocrinol., 2005, vol. 19, no. 5, pp. 1181–1190.

    Article  PubMed  CAS  Google Scholar 

  • Erikoglu, M., Sahin, M., Ozer, S., et al., Effects of Gender on the Severity of Sepsis, Surg. Today, 2005, vol. 35, no. 6, pp. 467–472.

    Article  PubMed  CAS  Google Scholar 

  • Faulkner, L., Altmann, D.M., Ellmerich, S., et al., Sexual Dimorphism in Superantigen Shock Involves Elevated TNF-Alpha and TNF-Alpha Induced Hepatic Apoptosis, Am. J. Respir. Crit. Care Med., 2007, vol. 176, no. 5, pp. 473–482.

    Article  PubMed  CAS  Google Scholar 

  • Fischer, L.M. Kwock, L., et al., Sex and Menopausal Status Influence Human Dietary Requirements for the Nutrient Choline, Am. J. Clin. Nutr., 2007, vol. 85, no. 5, pp. 1275–1285.

    PubMed  CAS  Google Scholar 

  • Flores-Morales, A., Greenhalgh, C.J., Norstedt, G., et al., Negative Regulation of Growth Hormone Receptor Signaling, Mol. Endocrinol., 2006, vol. 20, no. 2, pp. 241–253.

    Article  PubMed  CAS  Google Scholar 

  • Gardmo, C. and Mode, A., In vivo Transfection of Rat Liver Discloses Binding Sites Conveying GH-Dependent and Female-Specific Gene Expression, J. Mol. Endocrinol., 2006, vol. 37, pp. 433–441.

    Article  PubMed  CAS  Google Scholar 

  • Gardmo, C., Persson, B., and Mode, A., Cloning of a Novel Growth Hormone-Regulated Rat Complementary Deoxyribonucleic Acid with Homology to the Human Alpha1B-Glycoprotein, Characterizing a New Protein Family, Endocrinology, 2001, vol. 42, no. 6, pp. 2695–2701.

    Article  Google Scholar 

  • Gebert, C.A., Park, S.H., and Waxman, D.J., Down-Regulation of Liver JAK2-STAT5b Signaling by the Female Plasma Pattern of Continuous Growth Hormone Stimulation, Mol. Endocrinol., 1999, vol. 13, no. 2, pp. 213–227.

    Article  PubMed  CAS  Google Scholar 

  • Giannitrapani, L., Soresi, M., La Spada, E., et al., Sex Hormones and Risk of Liver Tumor, Ann. N.Y. Acad. Sci., 2006, vol. 1089, pp. 228–236.

    Article  PubMed  CAS  Google Scholar 

  • Gibney, J., Johannsson, G., Leung, K.C., et al., Comparison of the Metabolic Effects of Raloxifene and Oral Estrogen in Postmenopausal and Growth Hormone-Deficient Women, J. Clin. Endocrinol. Metab., 2005, vol. 90, no. 7, pp. 3897–3903.

    Article  PubMed  CAS  Google Scholar 

  • Gonçalves, I., Alves, C.H., Quintela, T., et al., Transthyretin is Up-Regulated by Sex Hormones in Mice Liver, Mol. Cell. Biochem., 2008, vol. 317, nos. 1–2, pp. 137–142.

    Article  PubMed  CAS  Google Scholar 

  • Goncharov, N.P., Katsiya, G.V., and Nizhnik, A.N., Formula zhizni. Degidroepiandrosteron: svoistva, metabolizm, biologicheskoe znachenie (Life Formula. Dehydroepiandrosterone: Properties, Metabolism, and Biological Role), Moscow: Izdat. Tovarishch. Adamant, 2004.

    Google Scholar 

  • Groos, J., Bannasch, P., Schwarz, M., et al., Comparison of Mode of Action of Four Hepatocarcinogens: a Model-Based Approach, Toxicol. Sci., 2007, vol. 99, no. 2, pp. 446–454.

    Article  PubMed  CAS  Google Scholar 

  • Gupta, S., Pathak, R.U., and Kanungo, M.S., DNA Methylation Induced Changes in Chromatin Conformation of the Promoter of the Vitellogenin II Gene of Japanese Quail during Aging, Gene, 2006, vol. 377, pp. 159–168.

    Article  PubMed  CAS  Google Scholar 

  • Helander, H., Gustafsson, J.A., and Mode, A., Possible Involvement of Truncated Signal Transducer and Activator of Transcription-5 in the GH Pattern-Dependent Regulation of CYP2C12 Gene Expression in Rat Liver, Mol. Endocrinol., 2002, vol. 16, no. 7, pp. 1598–1611.

    Article  PubMed  CAS  Google Scholar 

  • Higashi, E., Fukami, T., Itoh, M., et al., Human CYP2A6 is Induced by Estrogen via Estrogen Receptor, Drug Metab. Dispos., 2007, vol. 35, no. 10, pp. 1935–1941.

    Article  PubMed  CAS  Google Scholar 

  • Hinchliffe, S.A., Woods, S., Gray, S., et al., Cellular Distribution of Androgen Receptors in the Liver, J. Clin. Pathol., 1996, vol. 49, no. 5, pp. 418–420.

    Article  PubMed  CAS  Google Scholar 

  • Ho, K.K., Gibney, J., Johannsson, G., et al., Regulating of Growth Hormone Sensitivity by Sex Steroids: Implications for Therapy, Front. Horm. Res., 2006, vol. 35, pp. 115–128.

    Article  PubMed  CAS  Google Scholar 

  • Holloway, M.G., Miles, G.D., Dombkowski, A.A., et al., Liver-Specific HNF4{Alpha}-Deficiency: Greater Impact on Gene Expression in Male than in Female Mouse Liver, Mol. Endocrinol., 2008, vol. 22, no. 5, pp. 1274–1286.

    Article  PubMed  CAS  Google Scholar 

  • Itagaki, T., Shimizu, I., Cheng, X., et al., Opposing Effects of Oestradiol and Progesterone on Intracellular Pathways and Activation Processes in the Oxidative Stress Induced Activation of Cultured Rat Hepatic Stellate Cells, Gut, 2005, vol. 54, no. 12, pp. 1782–1789.

    Article  PubMed  CAS  Google Scholar 

  • Jahn, G.A., Daniel, N., Jolivet, G., et al., In vivo Study of Prolactin (PRL) Intracellular Signalling during Lactogenesis in the Rat: JAK/STAT Pathway is Activated by PRL in the Mammary Gland but Not in the Liver, Biol. Reprod., 1997, vol. 57, no. 4, pp. 894–900.

    Article  PubMed  CAS  Google Scholar 

  • Jansson, J.O., Eden, S., and Isaksson, O., Sexual Dimorphism in the Control of Growth Hormone Secretion, Endocrinol. Rev., 1985, vol. 6, no. 2, pp. 128–150.

    Article  CAS  Google Scholar 

  • Kang, J.S., Ahn, B., Kim, C.K., et al., Suppression of Chemically-Induced Liver Tumors by Castration or Estradiol-3-Benczoate Treatment in F344 Rats, Oncol. Rep., 2005, vol. 14, no. 2, pp. 377–382.

    PubMed  CAS  Google Scholar 

  • Kawai, T., Yokoyama, Y., Kawai, S., et al., Does Estrogen Contribute to the Hepatic Regeneration Following Portal Branch Ligation in Rats?, Am. J. Physiol. Gastrointest. Liver Physiol., 2007, vol. 292, no. 2, pp. G582–589.

    Article  PubMed  CAS  Google Scholar 

  • Kloet, E.R., De. Hormones, Brain and Stress, Endocrinol. Regul., 2003, vol. 37, no. 2, pp. 51–68.

    Google Scholar 

  • Kotokorpi, P., Gardmo, C., Nystrom, C.S., et al., Activation of the Glucocorticoid Receptor Or Liver X Receptors Interferes with Growth Hormone-Induced Akr1b7 Gene Expression in Rat Hepatocytes, Endocrinology, 2004, vol. 145, no. 12, pp. 5704–5713.

    Article  PubMed  CAS  Google Scholar 

  • Kovtun, I.V., Smirnov, A.N., Turovetskii, V.B., and Smirnova, O.V., Immunohistochemical Identification of Androgen Receptors in the Liver of Mature Male Rats, Byull. Eksp. Biol. Med., 1996, vol. 122, no. 8, pp. 193–196.

    CAS  Google Scholar 

  • Krebs, D.L. and Hilton, D.J., SOCS Proteins: Negative Regulators of Cytokine Signaling, Stem Cells, 2001, vol. 19, no. 5, pp. 378–387.

    Article  PubMed  CAS  Google Scholar 

  • Lamba, V., Lamba, J., Yasuda, K., et al., Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship to CYP2B6 Genotype and CAR (Constitutive Androstane Receptor) Expression, J. Pharmacol. Exp. Ther., 2003, vol. 307, no. 3, pp. 906–922.

    Article  PubMed  CAS  Google Scholar 

  • Landsman, T. and Waxman, D.J., Role of the Cytokine-Induced SH2 Domain-Containing Protein CIS in Growth Hormone Receptor Internalization, J. Biol. Chem., 2005, vol. 280, no. 45, pp. 37471–37480.

    Article  PubMed  CAS  Google Scholar 

  • Laz, E.V., Wiwi, C.A., and Waxman, D.J., Sexual Dimorphism of Rat Liver Nuclear Proteins: Regulatory Role of Growth Hormone, Mol. Cell. Proteomics, 2004, vol. 3, no. 12, pp. 1170–1180.

    Article  PubMed  CAS  Google Scholar 

  • Le Stunff, C., Gronowski, A.M., and Rotwein, P., Contrasting Acute in vivo Nuclear Actions of Growth Hormone and Prolactin, Mol. Cell. Endocrinol., 1996, vol. 121, no. 2, pp. 109–117.

    Article  PubMed  Google Scholar 

  • Legraverend, C., Mode, A., Wells, T., et al., Hepatic Steroid Hydroxylating Enzymes are Controlled by the Sexually Dimorphic Pattern of Growth Hormone Secretion in Normal and Dwarf Rats, FASEB J., 1992, vol. 6, no. 2, pp. 711–718.

    PubMed  CAS  Google Scholar 

  • Leong, G.M., Moverare, S., Brce, J., et al., Estrogen Up-Regulates Hepatic Expression of Suppressors of Cytokine Signaling-2 and -3 in vivo and in vitro, Endocrinology, 2004, vol. 145, no. 12, pp. 5525–5531.

    Article  PubMed  CAS  Google Scholar 

  • Leung, K.C., Doyle, N., Ballesteros, M., et al., Estrogen Inhibits GH Signaling by Suppressing GH-Induced JAK2 Phosphorylation, an Effect Mediated by SOCS-2, Proc. Natl. Acad. Sci. USA, 2003, vol. 100, no. 3, pp. 1016–1021.

    Article  PubMed  CAS  Google Scholar 

  • Leung, K.C., Johannsson, G., Leong, G.M., et al., Estrogen Regulation of Growth Hormone Action, Endocrinol. Rev., 2004, vol. 25, no. 5, pp. 693–721.

    Article  CAS  Google Scholar 

  • Li, Z., Agellon, L.B., and Vance, D.E., A Role for High Density Lipoproteins in Hepatic Phosphatidylcholine Homeostasis, Biochim. Biophys. Acta, 2007, vol. 1771, no. 7, pp. 893–900.

    PubMed  CAS  Google Scholar 

  • Lu, P., Liu, F., Wang, C.Y., et al., Gender Differences in Hepatic Ischemic Reperfusion Injury in Rats are Associated with Endothelial Cell Nitric Oxide Synthase-Derived Nitric Oxide, World J. Gastroenterol., 2005, vol. 11, no. 22, pp. 3441–3445.

    PubMed  CAS  Google Scholar 

  • Lu, S., Jenster, G., and Epner, D.E., Androgen Induction of Cyclin-Dependent Kinase Inhibitor P21 Gene: Role of Androgen Receptor and Transcription Factor Sp1 Complex, Mol. Endocrinol., 2000, vol. 14, no. 5, pp. 753–760.

    Article  PubMed  CAS  Google Scholar 

  • Marassi, M.P., Fortunato, R.S., Silva, A.C., et al., Sexual Dimorphism in Thyroid Function and Type 1 Iodothyronine Deiodinase Activity in Pre-Pubertal and Adult Rats, J. Endocrinol., 2007, vol. 192, no. 1, pp. 121–130.

    Article  PubMed  CAS  Google Scholar 

  • McConnachie, L.A., Mohar, I., Hudson, F.N., et al., Glutamate Cysteine Ligase Modifier Subunit Deficiency and Gender as Determinants of Acetaminophen-Induced Hepatotoxicity in Mice, Toxicol. Sci., 2007, vol. 99, no. 2, pp. 628–636.

    Article  PubMed  CAS  Google Scholar 

  • Meinhardt, U.J. and Ho, K.K., Regulation of Growth Hormone Action by Gonadal Steroids, Endocrinol. Metab. Clin. North Am., 2007, vol. 36, no. 1, pp. 57–73.

    Article  PubMed  CAS  Google Scholar 

  • Morozov, I.A., Astapova, I.I., Smirnov, A.N., et al., Localization of Matrix-Associated Elements in the 5′-Region of the Rat Estrogen Sulfotransferase Gene, Bioorg. Khim., 2004, vol. 30, no. 4, pp. 389–393.

    PubMed  CAS  Google Scholar 

  • Nagoshi, S., Sex- or Gender-Specific Medicine in Hepatology, Hepatol. Res., 2008, vol. 38, no. 3, pp. 219–224.

    Article  PubMed  Google Scholar 

  • Naugler, W.E., Sakurai, T., Kim, S., et al., Gender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production, Science, 2007, vol. 317, no. 5834, pp. 121–124.

    Article  PubMed  CAS  Google Scholar 

  • Ostroukhova, T.Yu., Kurasheva, O.Yu., Rozenkrants, A.A., et al., Increased Sex-Dependent Expression of Prolactin Receptors after Intrahepatic Transplantation of H27 Rat Hepatoma Cells, Byull. Eksp. Biol. Med., 2007, vol. 143, no. 3, pp. 276–279.

    Article  CAS  Google Scholar 

  • Park, S.H. and Waxman, D.J., Inhibitory Cross-Talk between STAT5b and Liver Nuclear Factor HNF3beta: Impact on the Regulation of Growth Hormone Pulse-Stimulated, Male-Specific Liver Cytochrome P450 Gene Expression, J. High Resolut. Chromatogr. Chromatogr. Commun., 2001, vol. 276, no. 46, pp. 43031–43039.

    CAS  Google Scholar 

  • Park, S.H., Liu, X., Hennighausen, L., et al., Distinctive Roles of STAT5a and STAT5b in Sexual Dimorphism of Hepatic P450 Gene Expression. Impact of STAT5a Gene Disruption, J. Biol. Chem., 1999, vol. 274, no. 11, pp. 7421–7430.

    Article  PubMed  CAS  Google Scholar 

  • Perrot-Applanat, M., Gualillo, O., Pezet, A., et al., Dominant Negative and Cooperative Effects of Mutant Forms of Prolactin Receptor, Mol. Endocrinol., 1997, vol. 11, no. 8, pp. 1020–1032.

    Article  PubMed  CAS  Google Scholar 

  • Piccoletti, R., Bendinelli, P., and Maroni, P., Signal Transduction Pathway of Prolactin in Rat Liver, Mol. Cell. Endocrinol., 1997, vol. 135, no. 2, pp. 169–177.

    Article  PubMed  CAS  Google Scholar 

  • Quintanilla, M.E., Tampier, L., Sapag, A., et al., Sex Differences, Alcohol Dehydrogenase, Acetaldehyde Burst, and Aversion to Ethanol in the Rat: a Systems Perspective, Am. J. Physiol. Endocrinol. Metab., 2007, vol. 293, no. 2, pp. E531–537.

    Article  PubMed  CAS  Google Scholar 

  • Raddatz, D., Henneken, M., Armbrust, T., et al., Subcellular Distribution of Glucocorticoid Receptor in Cultured Rat and Human Liver-Derived Cells and Cell Lines: Influence of Dexamethasone, Hepatology, 1996, vol. 24, no. 4, pp. 928–933.

    Article  PubMed  CAS  Google Scholar 

  • Ram, P.A., Park, S.H., Choi, H.K., et al., Growth Hormone Activation of Stat 1, Stat 3, and Stat 5 in Rat Liver. Differential Kinetics of Hormone Desensitization and Growth Hormone Stimulation of Both Tyrosine Phosphorylation and Serine/Threonine Phosphorylation, J. Biol. Chem., 1996, vol. 271, no. 10, pp. 5929–5940.

    Article  PubMed  CAS  Google Scholar 

  • Ramaiah, S.K. and Rittling, S., Role of Osteopontin in Regulating Hepatic Inflammatory Responses and Toxic Liver Injury, Exp. Opin. Drug Metab. Toxicol., 2007, vol. 3, no. 4, pp. 519–526.

    Article  CAS  Google Scholar 

  • Rogers, A.B., Theve, E.J., Feng, Y., et al., Hepatocellular Carcinoma Associated with Liver-Gender Disruption in Male Mice, Cancer Res., 2007, vol. 67, no. 24, pp. 11536–11546.

    Article  PubMed  CAS  Google Scholar 

  • Rozen, V.B., Mataradze, G.D., Smirnova, O.V., et al., Polovaya differentsirovka funktsii pecheni (Sex Differentiation of Hepatic Functions), Moscow: Meditsina, 1991.

    Google Scholar 

  • Rundlett, S.E. and Miesfeld, R.L., Quantitative Differences in Androgen and Glucocorticoid Receptor DNA Binding Properties Contribute to Receptor-Selective Transcriptional Regulation, Mol. Cell. Endocrinol., 1995, vol. 109, no. 1, pp. 1–10.

    Article  PubMed  CAS  Google Scholar 

  • Safe, S. and Kim, K., Non-Classical Genomic Estrogen Receptor (ER)/Specificity Protein and ER/Activating Protein-1 Signaling Pathways, J. Mol. Endocrinol., 2008, vol. 41, no. 5, pp. 263–275.

    Article  PubMed  CAS  Google Scholar 

  • Sasaki, Y., Takahashi, Y., Nakayama, K., et al., Cooperative Regulation of CYP2C12 Gene Expression by STAT5 and Liver-Specific Factors in Female Rats, J. Biol. Chem., 1999, vol. 274, no. 52, pp. 37117–37124.

    Article  PubMed  CAS  Google Scholar 

  • Schirmer, B.D., Winters, K.L., and Edlich, R.F., Cholelithiasis and Cholecystitis, J. Long Term Eff. Med. Implants, 2005, vol. 15, no. 3, pp. 329–338.

    Article  PubMed  Google Scholar 

  • Schirmer, M., Rosenberger, A., Klein, K., et al., Sex-Dependent Genetic Markers of CYP3A4 Expression and Activity in Human Liver Microsomes, Pharmacogenomics, 2007, vol. 8, no. 5, pp. 443–453.

    Article  PubMed  CAS  Google Scholar 

  • Sharma, M.R., Polavarapu, R., Roseman, D., et al., Increased Severity of Alcoholic Liver Injury in Female Versus Male Rats: a Microarray Analysis, Exp. Mol. Pathol., 2008, vol. 84, no. 1, pp. 46–58.

    Article  PubMed  CAS  Google Scholar 

  • Shchelkunova, T.A. and Smirnov, A.N., Expression of the Specific Estrogen-Binding Protein in the Liver of the Androgenized Mature Female Rats during Liver Regeneration after CCl4 Intoxication, Byull. Eksp. Biol. Med., 1996, vol. 122, no. 7, pp. 28–31.

    CAS  Google Scholar 

  • Shimizu, I., Kohno, N., Tamaki, K., et al., Female Hepatology: Favorable Role of Estrogen in Chronic Liver Disease with Hepatitis B Virus Infection, World J. Gastroenterol., 2007, vol. 13, no. 32, pp. 4295–4305.

    PubMed  CAS  Google Scholar 

  • Shin, Y., Vaziri, N.D., Willekes, N., et al., Effects of Gender on Hepatic HMG-CoA Reductase, Cholesterol Alpha-Hydroxylase, and LDL Receptor in Hereditary Analbuminemia, Am. J. Physiol. Endocrinol. Metab., 2005, vol. 289, no. 6, pp. E993–998.

    Article  PubMed  CAS  Google Scholar 

  • Shirota, M., Banville, D., Ali, S., et al., Expression of Two Forms of Prolactin Receptor in Rat Ovary and Liver, Mol. Endocrinol., 1990, vol. 4, no. 8, pp. 1136–1143.

    Article  PubMed  CAS  Google Scholar 

  • Simon, F.R., Fortune, J., Iwahashi, M., et al., Multihormonal Regulation of Hepatic Sinusoidal Ntcp Gene Expression, Am. J. Physiol. Gastrointest. Liver Physiol., 2004, vol. 287, no. 4, pp. G782–794.

    Article  PubMed  CAS  Google Scholar 

  • Smirnov, A.N., Membrane Localization of the Nuclear Receptor: A Paradox with Important Consequences, Ros. Fiziol. Zh. im. I.M. Sechenova, 2005, vol. 91, no. 1, pp. 31–45.

    CAS  Google Scholar 

  • Smirnov, A.N., Smirnova, O.V., and Rozen, V.B., Detection and Preliminary Characterization of a Particular Estrogen-Binding Protein in the Liver of Male Rats, Biokhimiya, 1977, vol. 42, no. 3, pp. 560–571.

    CAS  Google Scholar 

  • Smirnov, A.N., Nuclear Receptors: Nomenclature, Ligands, and Mechanisms of Their Effects on Gene Expression (a Review), Biokhimiya, 2002, vol. 67, no. 9, pp. 1157–1181.

    Google Scholar 

  • Smirnova, O.V. and Bogorad, R.L., Short Forms of Membrane Receptors: Generation and Role in Hormonal Signal Transduction, Biokhimiya, 2004, vol. 69, no. 4, pp. 437–452.

    Google Scholar 

  • Smirnova, O.V., Kovtun, I.V., Smirnov, A.N., et al., Inheritance of Androgen Program of Male-Specific Expression of Unusual Estrogen-Binding Protein by Daughter Hepatocytes at Rat Liver Regeneration, J. High Resolut. Chromatogr. Chromatogr. Commun., 1993, vol. 44, no. 2, pp. 155–162.

    CAS  Google Scholar 

  • Smirnova, O.V., Oleinik, N.V., and Rozen, V.B., Regularities in Androgen Reception in Rat Liver and Its Role in Realizing Direct Androgenous Effects, Biokhimiya, 1991, vol. 56, no. 4, pp. 681–686.

    CAS  Google Scholar 

  • Smirnova, O.V., Vishnyakova, T.G., Bocharov, A.V., et al., Evidence for Direct Action of Testosterone on Rat Liver Cells: in vivo and in vitro Induction of Unusual Estrogen-Binding Protein, J. Steroid Biochem. Mol. Biol., 1992, vol. 42, no. 2, pp. 243–249.

    Article  PubMed  CAS  Google Scholar 

  • Smirnova, O.V., Vishnyakova, T.G., Rozen, V.B., et al., In vivo and in vitro Estimations of the Direct Effect of Estrogen on Rat Hepatocytes Tested by the Changes in the Unusual Estrogen-Binding Protein Content, J. High Resolut. Chromatogr. Chromatogr. Commun., 1990, vol. 35, nos. 3–4, pp. 457–463.

    CAS  Google Scholar 

  • Smirnova, O.V., Vishnyakova, T.G., Smirnov, A.N., et al., The Unusual Estrogen-Binding Protein (UEBP) of Rat Liver: the Role of Sex Steroids and Hypophysis in Its Regulation, J. Steroid Biochem., 1985, vol. 23, no. 4, pp. 461–468.

    Article  PubMed  CAS  Google Scholar 

  • Smirnova, O.V., Vishnyakova, T.G., and Rozen, V.B., Role of Various Hormones of Total Metabolic Action in the Expression of Sex Differentiation of the Rat Liver by a Specific Estrogen-Binding Protein, Probl. Endokrinol.(Moscow), 1989, vol. 35, no. 3, pp. 59–63.

    CAS  Google Scholar 

  • Soldaini, E., John, S., Moro, S., et al., DNA Binding Site Selection of Dimeric and Tetrameric Stat5 Proteins Reveals a Large Repertoire of Divergent Tetrameric Stat5a Binding Sites, Mol. Cell. Biol., 2000, vol. 20, no. 1, pp. 389–401.

    Article  PubMed  CAS  Google Scholar 

  • Soric, S., Belanger, M.P., Askin, N., et al., Impact of Female Sex Hormones on Liver Tissue Lactic Acidosis During Ischemia, Transplantation, 2007, vol. 84, no. 6, pp. 763–770.

    Article  PubMed  CAS  Google Scholar 

  • Stopková, R., Stopka, P., Janotová, K., et al., Species-Specific Expression of Major Urinary Proteins in the House Mice (Mus musculus musculus and Mus musculus domesticus), J. Chem. Ecol., 2007, vol. 33, no. 4, pp. 861–869.

    Article  PubMed  CAS  Google Scholar 

  • Tanaka, M., Suzuki, M., Kawana, T., et al., Differential Effects of Sex Steroid Hormones on the Expression of Multiple First Exons Including a Novel First Exon of Prolactin Receptor Gene in the Rat Liver, J. Mol. Endocrinol., 2005, vol. 34, no. 3, pp. 667–673.

    Article  PubMed  CAS  Google Scholar 

  • Tang, W., Norlin, M., and Wikvall, K., Regulation of Human CYP27A1 by Estrogens and Androgens in HepG2 and Prostate Cells, Arch. Biochem. Biophys., 2007, vol. 462, no. 1, pp. 13–20.

    Article  PubMed  CAS  Google Scholar 

  • Thangavel, C. and Shapiro, B.H., A Molecular Basis for the Sexually Dimorphic Response to Growth Hormone, Endocrinology, 2007, vol. 148, no. 6, pp. 2894–2903.

    Article  PubMed  CAS  Google Scholar 

  • Thangavel, C. and Shapiro, B.H., Inherent Sexually Dimorphic Expression of Hepatic CYP2C12 Correlated with Repressed Activation of Growth Hormone-Regulated Signal Transduction in Male Rats, Drug Metab. Dispos., 2008, vol. 36, no. 9, pp. 1884–1895.

    Article  PubMed  CAS  Google Scholar 

  • Thangavel, C., Dhir, R.N., Volgin, D.V., et al., Sex-Dependent Expression of CYP2C11 in Spleen, Thymus and Bone Marrow Regulated by Growth Hormone, Biochem. Pharmacol., 2007, vol. 74, no. 10, pp. 1476–1484.

    Article  PubMed  CAS  Google Scholar 

  • Thangavel, C., Dworakowski, W., and Shapiro, B.H., Inducibility of Male-Specific Isoforms of Cytochrome P450 by Sex-Dependent Growth Hormone Profiles in Hepatocyte Cultures from Male but not Female Rats, Drug Metab. Dispos., 2006, vol. 34, no. 3, pp. 410–419.

    PubMed  CAS  Google Scholar 

  • Trott, J.F., Hovey, R.C., Koduri, S., et al., Alternative Splicing to Exon 11 of Human Prolactin Receptor Gene Results in Multiple Isoforms Including a Secreted Prolactin-Binding Protein, J. Mol. Endocrinol., 2003, vol. 30, no. 1, pp. 31–47.

    Article  PubMed  CAS  Google Scholar 

  • Verdier, F., Rabionet, R., Gouilleux, F., et al., A Sequence of the CIS Gene Promoter Interacts Preferentially with Two Associated STAT5A Dimers: A Distinct Biochemical Difference between STAT5A and STAT5B, Mol. Cell. Biol., 1998, vol. 18, no. 10, pp. 5852–5860.

    PubMed  CAS  Google Scholar 

  • Verma, A.S., Dhir, R.N., and Shapiro, B.H., Inadequacy of the Janus Kinase 2/Signal Transducer and Activator of Transcription Signal Transduction Pathway to Mediate Episodic Growth Hormone-Dependent Regulation of Hepatic CYP2C11, Mol. Pharmacol., 2005, vol. 67, no. 3, pp. 891–901.

    Article  PubMed  CAS  Google Scholar 

  • Vickers, A.E. and Lucier, G.W., Estrogen Receptor Levels and Occupancy in Hepatic Sinusoidal Endothelial and Kupffer Cells are Enhanced by Initiation with Diethylnitrosamine and Promotion with 17alpha-Ethinylestradiol in Rats, Carcinogenesis, 1996, vol. 17, no. 6, pp. 1235–1242.

    Article  PubMed  CAS  Google Scholar 

  • Wagnerberger, S., Schafer, C., Schwarz, E., et al., Is Nutrient Intake a Gender-Specific Cause for Enhanced Susceptibility to Alcohol-Induced Liver Disease in Women?, Alcohol Alcohol, 2008, vol. 43, no. 1, pp. 9–14.

    PubMed  CAS  Google Scholar 

  • Wang, A.G., Lee, K.Y., Kim, S.Y., et al., The Expression of Estrogen Receptors in Hepatocellular Carcinoma in Korean Patients, Yonsei Med. J, 2006a, vol. 47, no. 6, pp. 811–816.

    Article  PubMed  CAS  Google Scholar 

  • Wang, Y. and Cheng, C.H., ERalpha and STAT5a Cross-Talk: Interaction Through C-Terminal Portions of the Proteins Decreases STAT5a Phosphorylation, Nuclear Translocation and DNA-Binding, FEBS Lett., 2004, vol. 572, nos. 1–3, pp. 238–244.

    Article  PubMed  CAS  Google Scholar 

  • Wang, Z., Zhang, X., Shen, P., et al., A Variant of Estrogen Receptor-{Alpha}, HER-{Alpha}36: Transduction of Estrogen- and Antiestrogen-Dependent Membrane-Initiated Mitogenic Signaling, Proc. Natl. Acad. Sci. USA, 2006b, vol. 103, no. 24, pp. 9063–9068.

    Article  PubMed  CAS  Google Scholar 

  • Waters, M.J., Hoang, H.N., Fairlie, D.P., et al., New Insights into Growth Hormone Action, J. Mol. Endocrinol., 2006, vol. 36, no. 1, pp. 1–7.

    Article  PubMed  CAS  Google Scholar 

  • Waxman, D.J. and O’Connor, C., Growth Hormone Regulation of Sex-Dependent Liver Gene Expression, Mol. Endocrinol., 2006, vol. 20, no. 11, pp. 2613–2629.

    Article  PubMed  CAS  Google Scholar 

  • Waxman, D.J., LeBlanc, G.A., Morrissey, J.J., et al., Adult Male-Specific and Neonatally Programmed Rat Hepatic P450 Forms RLM2 and 2a are Not Dependent on Pulsatile Plasma Growth Hormone for Expression, J. Biol. Chem., 1988, vol. 263, no. 23, pp. 11396–11406.

    PubMed  CAS  Google Scholar 

  • Waxman, D.J., Ram, P.A., Notani, G., et al., Pituitary Regulation of the Male-Specific Steroid 6 Beta-Hydroxylase P450 2a (Gene Product IIIA2) in Adult Rat Liver. Suppressive Influence of Growth Hormone and Thyroxine Acting at a Pretranslational Level, Mol. Endocrinol., 1990, vol. 4, no. 3, pp. 447–454.

    Article  PubMed  CAS  Google Scholar 

  • Webb, S.J., Geoghegan, T.E., Prough, R.A., et al., The Biological Actions of Dehydroepiandrosterone Involves Multiple Receptors, Drug Metab. Rev., 2006, vol. 38, nos. 1–2, pp. 89–116.

    Article  PubMed  CAS  Google Scholar 

  • Wiwi, C.A. and Waxman, D.J., Role of Hepatocyte Nuclear Factors in Transcriptional Regulation of Male-Specific CYP2A2, J. Biol. Chem., 2005, vol. 280, no. 5, pp. 3259–3268.

    Article  PubMed  CAS  Google Scholar 

  • Wiwi, C.A., Gupte, M., and Waxman, D.J., Sexually Dimorphic P450 Gene Expression in Liver-Specific Hepatocyte Nuclear Factor 4alpha-Deficient Mice, Mol. Endocrinol., 2004, vol. 18, no. 8, pp. 1975–1987.

    Article  PubMed  CAS  Google Scholar 

  • Wood, M., Ananthanarayanan, M., Jones, B., et al., Hormonal Regulation of Hepatic Organic Anion Transporting Polypeptides, Mol. Pharmacol., 2005, vol. 68, no. 1, pp. 218–225.

    PubMed  CAS  Google Scholar 

  • Xiao, F., Mirwald, A., Papaioannou, M., et al., Secretoglobin 2A1 is under Selective Androgen Control Mediated by a Peculiar Binding Site for Sp Family Transcription Factors, Mol. Endocrinol., 2005, vol. 19, no. 12, pp. 2964–2978.

    Article  PubMed  CAS  Google Scholar 

  • Yang, X., Schadt, E.E., Wang, S., et al., Tissue-Specific Expression and Regulation of Sexually Dimorphic Genes in Mice, Genome Res, 2006, vol. 16, no. 8, pp. 995–1004.

    Article  PubMed  CAS  Google Scholar 

  • Yokoyama, Y., Nagino, M., and Nimura, Y., Which Gender is Better Positioned in the Process of Liver Surgery? Male or Female?, Surg. Today, 2007, vol. 37, no. 10, pp. 823–830.

    Article  PubMed  Google Scholar 

  • Zandieh, Doulabi B., Platvoet-Ter Schiphorst M., Van Beeren H.C., et al., TR(Beta)1, Protein is Preferentially Expressed in the Pericentral Zone of Rat Liver and Exhibits Marked Diurnal Variation, Endocrinology, 2002, vol. 143, no. 3, pp. 979–984.

    Article  Google Scholar 

  • Zhou, Y., Shimizu, I., Lu, G., et al., Hepatic Stellate Cells Contain the Functional Estrogen Receptor Beta but not the Estrogen Receptor Alpha in Male and Female Rats, Biochem. Biophys. Res. Commun., 2001, vol. 286, no. 5, pp. 1059–1065.

    Article  PubMed  CAS  Google Scholar 

  • Zivna, H., Zivny, P., Palicka, V., et al., The Differences in Selected Biochemical Markers and Histological Findings After Bile Duct Ligation in Male and Female Rats, Adv. Clin. Path., 2001, vol. 5, no. 4, pp. 147–153.

    PubMed  CAS  Google Scholar 

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    A. N. Smirnov

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Original Russian Text © A.N. Smirnov, 2009, published in Ontogenez, 2009, Vol. 40, No. 5, pp. 334–354.

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Smirnov, A.N. Hormonal mechanisms of sex differentiation of the liver: the modern conception and problems. Russ J Dev Biol 40, 264–282 (2009). https://doi.org/10.1134/S1062360409050026

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