Organochlorine insecticides: impacts on human HepG2 cytochrome P4501A, 2B activities and glutathione levels

This study examined the effects of the organochlorine (OC) insecticides chlordane, o,p'-DDT, dieldrin, endosulfan, kepone, methoxychlor, and toxaphene on human HepG2 cytochrome P450 (IA-EROD and 2B-PROD) activities and glutathione (GSH) levels. Cells were exposed for 24h at high concentrations (1, 5 or 10mM) and for 48h at lower concentrations ranging from 0.01 to 1 mM to evaluate dose responses. Our results show that after 48h all but dieldrin significantly induced both P4501A and 2B. P4502B responses were greater at all exposure concentrations and times. Mixed responses in GSH levels were observed. All OCs except dieldrin and MXC significantly depleted GSH after 24 h. At 48 h, chlordane, endosulfan and toxaphene significantly increased GSH at low levels and decreased GSH at high levels, while kepone and methoxychlor produced significant declines in GSH at all concentrations. These results support findings of OC insecticides inducing CYP1A, 2B in rats, with CYP2B responses more important. GSH levels declined when P4502B activity was significantly elevated and were significantly increased in the absence of significant P450 activity, suggesting that GSH levels influence the catalytic activity of the cytochrome P450s and the cytochrome P450s influence the cell's ability to regulate GSH. (C) 2004 Elsevier Ltd. All rights reserved.