title: Cytochrome P450 isoforms are differently up-regulated in aflatoxin B₁-exposed human lymphocytes and monocytes.
abstract: BACKGROUND
  Aflatoxins (AFs) are highly hazardous mycotoxins with potent carcinogenic, mutagenic and immune disregulatory properties. Cytochrome P450 (CYP) isoforms are central for enhanced AFB₁ toxicity in situ. It remains to be seen whether and how these AFB₁ activators work in human leukocytes.
  
  
  OBJECTIVE
  To investigate the involvement of CYP isoforms in AFB₁ toxicity of circulating mononuclear cells, we examined the impact of environmentally relevant levels of AFB1 on lymphocytes and monocytes.
  
  
  METHODS
  Very low and moderate doses of AFB₁ with/without CYP inducers on transcription of key CYP isoforms and toll-like receptor 4 (TLR4) were examined in human lymphocytes, monocytes and HepG2 cells; cell cycle distribution and viability were also analyzed in AFB₁-exposed lymphocytes and monocytes.
  
  
  RESULTS
  Only CYP1A1, CYP1B1, CYP3A4, CYP3A5 and CYP3A7 expressed in lymphocytes and monocytes. TLR4 much more expressed in monocytes than in lymphocytes, but HepG2 showed little TLR4 transcription. While CYP1A1, CYP1B1 and CYP3A4 were highly induced by AFB₁ in monocytes, in lymphocytes only CYP1A1 was induced. Among CYP1A1, CYP1B1 and CYP3A4 only CYP1A1 responded to low and moderate levels of AFB₁. Enhanced transcripts of CYPs by AFB₁ yielded little synergies on TLR4 transcription in lymphocytes and monocytes. Cell cycle arrest and necrosis were also detected in AFB₁-exposed lymphocytes and monocytes.
  
  
  CONCLUSIONS
  Our novel findings indicate that AFB₁ more intensively stimulates CYP genes expression in monocytes than in lymphocytes. Mechanistically, this could explain a more pronounced immunotoxicity of AFB₁ in myeloid than in lymphoid lineage cells in vitro/situ/vivo.
authors.affiliation: Department of Pathobiology, Section Immunology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran .
authors.forename: Abbas
authors.initials: A
authors.lastname: Bahari
authors.forename: Jalil
authors.initials: J
authors.lastname: Mehrzad
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Mahmoudi
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Bassami
authors.forename: Hesam
authors.initials: H
authors.lastname: Dehghani
mesh_terms: D000293:Adolescent; D000328:Adult; D016604:Aflatoxin B1 / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D008214:Lymphocytes / Q000166:cytology / Q000201:enzymology*; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000201:enzymology*; D011042:Poisons / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D007527:Isoenzymes; D011042:Poisons; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1