title: Modulation of cytochrome P450 2A5 activity by lipopolysaccharide: low-dose effects and non-monotonic dose-response relationship.
abstract: Mouse cytochrome P450 (CYP) 2A5 is induced by inflammatory conditions and infectious diseases that down-regulate the expression and activity of most other CYP isoforms. Enhanced oxidative stress and nuclear factor (erythroid 2-related factor) 2 (Nrf2) transcription factor activation have been hypothesised to mediate up-regulation of CYP2A5 expression in the murine liver. The unique and complex regulation of CYP2A5, however, is far from being thoroughly elucidated. Sepsis and high doses of bacterial lipopolysaccharide (LPS) elicit oxidative stress in the liver, but depression, not induction, of CYP2A5 has been observed in studies of mice treated with LPS. The foregoing facts prompted us to evaluate the response of CYP2A5 liver activity in female DBA-2 mice over a broad range of LPS doses (0, 0.025, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10, and 20 mg/kg). Cytokine levels (interleukin [IL]-2, IL-4, IL-6, IL-10, IL-17A, interferon gamma, tumour necrosis factor alpha) and nitric oxide (NO) were measured in the blood serum. Activities of CYP1A (EROD) and CYP2B (BROD) in the liver were also determined for comparative purposes. LPS depressed CYP2A5 at low doses (0.025-2.0 mg/kg) but not at doses (>2 mg/kg) that increased pro-inflammatory cytokines and NO serum levels, and depressed CYP1A and CYP2B activities. Blockade of pro-inflammatory cytokines and the overproduction of NO induced by co-treatment with pentoxifylline and LPS and iNOS inhibition with aminoguanidine both extended down-regulation of CYP2A5 to the high dose range while not affecting LPS-induced depression of CYP1A and CYP2B. Overall, the results suggested that NO plays a role in the reversal of the low-dose LPS-induced depression of CYP2A5 observed when mice were challenged with higher doses of LPS.
authors: Laboratory of Environmental Toxicology, Department of Biological Sciences, National School of Public Health, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, 21040-361, Brazil.
authors: Ana C A X
authors: AC
authors: De-Oliveira
authors: Laboratory of Environmental Toxicology, Department of Biological Sciences, National School of Public Health, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, 21040-361, Brazil.
authors: Kátia S
authors: KS
authors: Poça
authors: Laboratory of Malaria Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, 21040-361, Brazil.
authors: Paulo R R
authors: PR
authors: Totino
authors: Laboratory of Environmental Toxicology, Department of Biological Sciences, National School of Public Health, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, 21040-361, Brazil.
authors: Francisco J R
authors: FJ
authors: Paumgartten
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D051379:Mice; D009569:Nitric Oxide / Q000097:blood
chemical_list: D016207:Cytokines; D006146:Guanidines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D000072467:Cytochrome P450 Family 2; C004479:pimagedine
references: Biochem Pharmacol. 2008 Mar 1;75(5):1230-9
references: 18068688
references: Free Radic Biol Med. 2002 Nov 1;33(9):1173-85
references: 12398925
references: Toxicology. 2003 Mar 3;184(2-3):211-26
references: 12499123
references: J Pharmacol Exp Ther. 2004 Feb;308(2):600-8
references: 14610226
references: Toxicol Appl Pharmacol. 2008 Oct 1;232(1):135-41
references: 18602936
references: Malar J. 2010;9:81
references: 20307316
references: Curr Drug Metab. 2011 Feb;12(2):186-97
references: 21395539
references: Nitric Oxide. 2011 Aug 1;25(2):161-8
references: 21703357
references: Eur J Pharmacol. 2011 Sep 30;667(1-3):6-12
references: 21669194
references: Toxicol Appl Pharmacol. 2011 Nov 15;257(1):14-22
references: 21871474
references: J Biol Chem. 2012 Feb 10;287(7):4411-8
references: 22147701
references: J Biochem. 2012 Mar;151(3):217-9
references: 22210905
references: Toxicol Appl Pharmacol. 2012 May 15;261(1):50-8
references: 22465937
references: Curr Drug Metab. 2004 Jun;5(3):235-43
references: 15180493
references: Toxicol Appl Pharmacol. 2004 Sep 15;199(3):285-94
references: 15364544
references: Anal Biochem. 1976 May 7;72:248-54
references: 942051
references: Eur J Biochem. 1988 Jan 15;171(1-2):205-11
references: 3338462
references: Biochem Biophys Res Commun. 1989 Nov 30;165(1):284-91
references: 2590227
references: Biochem J. 1992 Aug 15;286 ( Pt 1):289-94
references: 1520280
references: Mol Carcinog. 1993;7(4):276-80
references: 8352886
references: Food Chem Toxicol. 1994 Apr;32(4):387-90
references: 8206435
references: Mol Carcinog. 1994 Oct;11(2):74-80
references: 7916995
references: Mol Carcinog. 1994 Oct;11(2):81-9
references: 7916996
references: Anal Biochem. 1994 Oct;222(1):217-23
references: 7856852
references: Hepatology. 1996 Sep;24(3):649-56
references: 8781338
references: Toxicol Lett. 1997 Jun 16;92(1):39-46
references: 9242356
references: Carcinogenesis. 1997 Nov;18(11):2179-90
references: 9395219
references: Drug Metab Rev. 1997 Nov;29(4):1129-88
references: 9421688
references: Mutagenesis. 1999 Mar;14(2):217-20
references: 10229924
references: Annu Rev Pharmacol Toxicol. 2006;46:123-49
references: 16402901
references: FEMS Immunol Med Microbiol. 2006 Jul;47(2):167-77
references: 16831203
references: Exp Parasitol. 2006 Aug;113(4):256-61
references: 16540109
references: Drug Metab Dispos. 2007 Jan;35(1):121-7
references: 17050650
references: Braz J Med Biol Res. 2007 May;40(5):657-62
references: 17464427
references: J Nutr. 2007 Jun;137(6 Suppl 2):1616S-1620S
references: 17513437
references: Biochem Pharmacol. 2008 Jan 15;75(2):538-51
references: 17945193
references: Toxicol Sci. 2012 Nov;130(1):132-44
references: 22859313
references: Curr Drug Metab. 2013 Jan;14(1):137-50
references: 22497566
references: Toxicol Appl Pharmacol. 2013 Jul 15;270(2):129-38
references: 23628428
references: J Exp Bot. 2014 Feb;65(2):527-38
references: 24288182