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Spink DC, Katz BH, Hussain MM, Spink BC, Wu SJ, Liu N, Pause R, Kaminsky LS: Induction of CYP1A1 and CYP1B1 in T-47D human breast cancer cells by benzo [a] pyrene is diminished by arsenite. Drug Metab Dispos. 2002 Mar;30(3):262-9.
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 NaAsO (2) 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 microM BAP; higher levels caused reduced rates of metabolism due to inhibition of CYP1A1 and CYP1B1. NaAsO (2) caused pronounced decreases in the induction of CYP1A1 and CYP1B1 by 3 microM BAP because cotreatment with 10 microM NaAsO (2) 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 NaAsO (2). The levels of the CYP1A1 and CYP1B1 mRNAs induced by BAP were not significantly affected by coexposure to NaAsO (2); however, heme oxygenase 1 mRNA levels were markedly induced by coexposure to BAP and NaAsO (2). 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. |
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