title: Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver.
abstract: CYP2E1 is of paramount toxicological significance because it metabolically activates a large number of low-molecular-weight toxicants and carcinogens. In this context, factors that interfere with Cyp2e1 regulation may critically affect xenobiotic toxicity and carcinogenicity. The aim of this study was to investigate the role of female steroid hormones in the regulation of CYP2E1, as estrogens and progesterone are the bases of contraceptives and hormonal replacement therapy in menopausal women. Interestingly, a fluctuation in the hepatic expression pattern of Cyp2e1 was revealed in the different phases of the estrous cycle of female mice, with higher Cyp2e1 expression at estrus (E) and lower at methestrus (ME), highly correlated with that in plasma gonadal hormone levels. Depletion of sex steroids by ovariectomy repressed Cyp2e1 expression to levels similar to those detected in males and cyclic females at ME. Hormonal supplementation brought Cyp2e1 expression back to levels detected at E. The role of progesterone appeared to be more prominent than that of 17β-estradiol. Progesterone-induced Cyp2e1 upregulation could be attributed to inactivation of the insulin/PI3K/Akt/FOXO1 signaling pathway. Tamoxifen, an anti-estrogen, repressed Cyp2e1 expression potentially via activation of the PI3K/Akt/FOXO1 and GH/STAT5b-linked pathways. The sex steroid hormone-related changes in hepatic Cyp2e1 expression were highly correlated with those observed in Hnf-1α, β-catenin, and Srebp-1c. In conclusion, female steroid hormones are clearly involved in the regulation of CYP2E1, thus affecting the metabolism of a plethora of toxicants and carcinogenic agents, conditions that may trigger several pathologies or exacerbate the outcomes of various pathophysiological states.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Ioannina, GR-45110, Ioannina, Greece. mkonstan@cc.uoi.gr
authors.forename: Maria
authors.initials: M
authors.lastname: Konstandi
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D030762:Estrous Cycle; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D050799:STAT5 Transcription Factor; D013629:Tamoxifen; D011374:Progesterone; D004958:Estradiol; D012313:RNA; D019392:Cytochrome P-450 CYP2E1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: 17β-estradiol; Cyp2e1; estrous cycle; mice; progesterone
references.citation: Arch Toxicol. 2009 Dec;83(12):1075-81
references.pmid: 19588123
references.citation: Toxicol Appl Pharmacol. 2007 May 15;221(1):102-10
references.pmid: 17397887
references.citation: Mol Pharmacol. 1986 Apr;29(4):399-404
references.pmid: 3702859
references.citation: J Biol Chem. 2008 Feb 8;283(6):3487-3496
references.pmid: 18056994
references.citation: Mol Endocrinol. 2006 Mar;20(3):647-60
references.pmid: 16239260
references.citation: Mol Endocrinol. 2006 Jun;20(6):1333-51
references.pmid: 16469768
references.citation: Endocrinology. 1989 Jun;124(6):2954-66
references.pmid: 2785912
references.citation: J Pharmacol Exp Ther. 1997 Dec;283(3):1479-85
references.pmid: 9400024
references.citation: Arch Biochem Biophys. 1999 Sep 1;369(1):11-23
references.pmid: 10462436
references.citation: Drug Metab Dispos. 2000 Feb;28(2):110-2
references.pmid: 10640505
references.citation: J Biol Chem. 1995 Dec 15;270(50):29632-5
references.pmid: 8530344
references.citation: Mol Pharmacol. 1990 Jan;37(1):119-29
references.pmid: 2105452
references.citation: J Gastroenterol Hepatol. 2006 Oct;21 Suppl 3:S22-5
references.pmid: 16958665
references.citation: Clin Pharmacol Ther. 1995 Jun;57(6):645-55
references.pmid: 7781264
references.citation: Endocrinology. 1999 Nov;140(11):5126-35
references.pmid: 10537141
references.citation: J Clin Endocrinol Metab. 2010 Jul;95(7 Suppl 1):s1-s66
references.pmid: 20566620
references.citation: Toxicol Appl Pharmacol. 2007 Aug 15;223(1):56-65
references.pmid: 17610925
references.citation: Biochem Biophys Res Commun. 1988 Aug 30;155(1):392-7
references.pmid: 3415695
references.citation: Endocr Rev. 2010 Feb;31(1):79-97
references.pmid: 19903932
references.citation: Int J Mol Med. 2007 Sep;20(3):351-8
references.pmid: 17671740
references.citation: Drug Metab Dispos. 2005 Mar;33(3):449-57
references.pmid: 15576447
references.citation: Mol Pharmacol. 2001 May;59(5):1138-46
references.pmid: 11306697
references.citation: Biol Reprod. 1981 May;24(4):784-94
references.pmid: 7195743
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6287-91
references.pmid: 10841534
references.citation: Cancer Res. 2008 Feb 1;68(3):826-33
references.pmid: 18245484
references.citation: Arch Biochem Biophys. 1988 May 15;263(1):29-35
references.pmid: 3285794
references.citation: J Pharmacol Exp Ther. 2002 Jan;300(1):273-81
references.pmid: 11752126
references.citation: Drug Metab Dispos. 1985 Sep-Oct;13(5):548-52
references.pmid: 2865101
references.citation: Trends Pharmacol Sci. 2004 Apr;25(4):193-200
references.pmid: 15063083
references.citation: J Biol Chem. 2005 Nov 4;280(44):36824-32
references.pmid: 16129680
references.citation: Mol Pharmacol. 1988 Feb;33(2):140-3
references.pmid: 3277033
references.citation: J Hepatol. 2009 Mar;50(3):572-83
references.pmid: 19157621
references.citation: J Clin Invest. 2000 Apr;105(8):1067-75
references.pmid: 10772651
references.citation: Endocr Rev. 2005 Dec;26(7):898-915
references.pmid: 16126938
references.citation: Mol Endocrinol. 2006 Nov;20(11):2613-29
references.pmid: 16543404
references.citation: Cell Signal. 1998 Oct;10(9):637-43
references.pmid: 9794245
references.citation: J Biol Chem. 1981 Dec 10;256(23):12068-75
references.pmid: 7298645
references.citation: Endocrine. 2003 Oct;22(1):25-40
references.pmid: 14610296
references.citation: Mol Endocrinol. 2010 Mar;24(3):667-78
references.pmid: 20150183
references.citation: Adv Exp Med Biol. 1991;283:753-8
references.pmid: 1648871
references.citation: Drug Metab Dispos. 2007 Jan;35(1):1-8
references.pmid: 17020953
references.citation: Drug Metab Rev. 2006;38(1-2):197-207
references.pmid: 16684657
references.citation: Endocrinology. 1992 Sep;131(3):1458-66
references.pmid: 1505477
references.citation: Mol Endocrinol. 2005 Feb;19(2):391-8
references.pmid: 15514031
references.citation: Xenobiotica. 1999 May;29(5):437-51
references.pmid: 10379983
references.citation: Br J Cancer. 2008 Oct 7;99(7):1056-63
references.pmid: 18797454
references.citation: J Mol Endocrinol. 2001 Aug;27(1):93-106
references.pmid: 11463580
references.citation: Drug Metab Dispos. 1994 Sep-Oct;22(5):806-10
references.pmid: 7835233
references.citation: J Pharmacol Exp Ther. 1997 Mar;280(3):1463-70
references.pmid: 9067336
references.citation: J Clin Endocrinol Metab. 1990 Oct;71(4):1036-40
references.pmid: 2205622
references.citation: J Biol Chem. 2002 Aug 23;277(34):30935-41
references.pmid: 12063252
references.citation: Arch Biochem Biophys. 1989 Feb 1;268(2):567-75
references.pmid: 2521554
references.citation: Poult Sci. 2003 Jan;82(1):54-61
references.pmid: 12580245
references.citation: Biotechnol Bioeng. 2002 Feb 15;77(4):462-6
references.pmid: 11787019
references.citation: Arch Biochem Biophys. 1990 Aug 15;281(1):132-8
references.pmid: 2116767
references.citation: Clin Pharmacol Ther. 2004 Dec;76(6):618-27
references.pmid: 15592333
references.citation: J Cell Biol. 2001 Jun 11;153(6):1161-74
references.pmid: 11402061
references.citation: Mol Pharmacol. 1992 Mar;41(3):474-9
references.pmid: 1545775
references.citation: Biol Reprod. 1996 Oct;55(4):762-8
references.pmid: 8879487
references.citation: Hepatology. 2002 Feb;35(2):263-73
references.pmid: 11826398
references.citation: Biochim Biophys Acta. 2003 Feb 17;1619(3):223-34
references.pmid: 12573481
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Nov;281(5):G1135-9
references.pmid: 11668021
references.citation: Hepatology. 1993 Dec;18(6):1483-9
references.pmid: 8244274
references.citation: Arch Biochem Biophys. 1997 Jan 15;337(2):239-50
references.pmid: 9016819
references.citation: Toxicol Lett. 1994 Feb 1;70(2):133-8
references.pmid: 8296317
references.citation: Biol Reprod. 2001 Sep;65(3):680-8
references.pmid: 11514328
references.citation: Mol Endocrinol. 1987 Aug;1(8):542-7
references.pmid: 3153476
references.citation: Drug Metab Rev. 1990;22(2-3):147-59
references.pmid: 2272285
references.citation: Steroids. 2009 Jan;74(1):20-9
references.pmid: 18831980
references.citation: Drug Metab Dispos. 1995 Mar;23(3):438-40
references.pmid: 7628313
references.citation: Mol Pharmacol. 2009 Aug;76(2):215-28
references.pmid: 19483103
references.citation: Chem Res Toxicol. 1991 Mar-Apr;4(2):168-79
references.pmid: 1664256
references.citation: Hepatology. 2006 Apr;43(4):817-25
references.pmid: 16557553
references.citation: Life Sci. 2008 Jan 2;82(1-2):1-10
references.pmid: 17988693
references.citation: Hepatology. 2005 Oct;42(4):905-14
references.pmid: 16175602
references.citation: J Hepatol. 2000 Jun;32(6):900-10
references.pmid: 10898310
references.citation: J Biol Chem. 1951 Nov;193(1):265-75
references.pmid: 14907713
references.citation: J Biol Chem. 2004 Sep 24;279(39):40255-8
references.pmid: 15304487
references.citation: Mol Pharmacol. 1998 Oct;54(4):740-7
references.pmid: 9765518
references.citation: Gen Comp Endocrinol. 2005 May 15;142(1-2):117-33
references.pmid: 15862556