TY - JOUR T1 - Induction of CYP1A1 and CYP1B1 in T-47D Human Breast Cancer Cells by Benzo[<em>a</em>]pyrene Is Diminished by Arsenite JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 262 LP - 269 DO - 10.1124/dmd.30.3.262 VL - 30 IS - 3 AU - David C. Spink AU - Barbara H. Katz AU - Mirza M. Hussain AU - Barbara C. Spink AU - Susan J. Wu AU - Ning Liu AU - Ronald Pause AU - Laurence S. Kaminsky Y1 - 2002/03/01 UR - http://dmd.aspetjournals.org/content/30/3/262.abstract N2 - Polycyclic aromatic hydrocarbons (PAHs) and metals are often environmental cocontaminants, yet there have been relatively few studies of combined effects of PAHs and metals on cytochrome P450 (P450)-catalyzed metabolism. We examined the effects of NaAsO2 in combination with benzo[a]pyrene (BAP) on CYP1A1 and CYP1B1 in T-47D human breast cancer cells by using estrogen metabolism as a probe of their activities. Exposure to BAP caused elevated rates of the 2- and 4-hydroxylation pathways of estrogen metabolism, indicating induction of both CYP1A1, an estradiol 2-hydroxylase, and CYP1B1, an estradiol 4-hydroxylase. BAP-induced metabolism peaked 9 to 16 h after exposure and returned to near-basal levels by 48 h. Concentration-response studies showed maximal induction of the 2- and 4-hydroxylation pathways at 3 μM BAP; higher levels caused reduced rates of metabolism due to inhibition of CYP1A1 and CYP1B1. NaAsO2 caused pronounced decreases in the induction of CYP1A1 and CYP1B1 by 3 μM BAP because cotreatment with 10 μM NaAsO2 inhibited the rates of the 2- and 4-hydroxylation pathways by 86 and 92%, respectively. Western immunoblots showed diminished levels of BAP-induced CYP1A1 by coexposure to NaAsO2. The levels of the CYP1A1 and CYP1B1 mRNAs induced by BAP were not significantly affected by coexposure to NaAsO2; however, heme oxygenase 1 mRNA levels were markedly induced by coexposure to BAP and NaAsO2. These results indicate a post-transcriptional inhibitory effect of arsenite on the expression of CYP1A1 and CYP1B1 in T-47D cells, possibly resulting from reduced heme availability. The American Society for Pharmacology and Experimental Therapeutics ER -