Cytochrome P450 isoforms are differently up-regulated in aflatoxin B1-exposed human lymphocytes and monocytes. (February 2014) - Bahari, Abbas
Abstract Context: 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. Materials and 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.